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Li, Jiayun, Zhikai Wang, and Douglas T. Fearon. "CD40 signaling induces type I interferon and immune control in mouse pancreatic cancer lacking the CXCL12-coat." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 241.37. http://dx.doi.org/10.4049/jimmunol.204.supp.241.37.
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Abstract Pancreatic ductal adenocarcinoma (PDA) has a low 5 year survival rate of 8.5% because of its late diagnosis and resistance to the existing therapies. Patients with PDA who are microsatellite stable do not respond to check point blockade immunotherapy due to impaired T cell infiltration, which is mediated by the CXCL12-coat on cancer cells (Wang Z, et al. bioRχiv). In mouse hepatic metastases established with PDA cells from the KPC model of PDA, Krt19-CRISPR/Cas9-edited tumors lacking the CXCL12-coat showed a type I interferon (IFN) response as well as T cell infiltration and activation compared to the control scramble tumors. By RNA FISH, we found that IFNb1 is dominantly produced by CD40+ cells, and not by SiglecH+ plasmacytoid dendritic cells. RNA sequencing data showed up-regulation of Cd40lg in the Krt19-edited tumors compared to the scramble tumors. Administration of antagonistic anti-CD40 antibody prior cancer cells inoculation abolished IFNb1 production, T cell accumulation and activation. To confirm the role of CD40, administration of agonistic anti-CD40 antibody to mice bearing wild type PDA tumors elicited intra-tumoral IFNb1 production in CD11b+ CD11c+ myeloid cells. The T cell infiltration and activation induced by agonistic anti-CD40 antibody treatment sensitized both subcutaneous pancreatic tumors and hepatic metastases to anti-PD1 treatment. These findings indicate that the expression of CD40L elicits an intra-tumoral type I IFN response that is required for immune control of PDA tumors in which CXCR4 signaling is impaired.
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Buchholz, David E., Thomas S. Carroll, Arif Kocabas, Xiaodong Zhu, Hourinaz Behesti, Phyllis L. Faust, Lauren Stalbow, Yin Fang, and Mary E. Hatten. "Novel genetic features of human and mouse Purkinje cell differentiation defined by comparative transcriptomics." Proceedings of the National Academy of Sciences 117, no. 26 (June 16, 2020): 15085–95. http://dx.doi.org/10.1073/pnas.2000102117.
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Comparative transcriptomics between differentiating human pluripotent stem cells (hPSCs) and developing mouse neurons offers a powerful approach to compare genetic and epigenetic pathways in human and mouse neurons. To analyze human Purkinje cell (PC) differentiation, we optimized a protocol to generate human pluripotent stem cell-derived Purkinje cells (hPSC-PCs) that formed synapses when cultured with mouse cerebellar glia and granule cells and fired large calcium currents, measured with the genetically encoded calcium indicator jRGECO1a. To directly compare global gene expression of hPSC-PCs with developing mouse PCs, we used translating ribosomal affinity purification (TRAP). As a first step, we usedTg(Pcp2-L10a-Egfp)TRAP mice to profile actively transcribed genes in developing postnatal mouse PCs and used metagene projection to identify the most salient patterns of PC gene expression over time. We then created a transgenicPcp2-L10a-EgfpTRAP hPSC line to profile gene expression in differentiating hPSC-PCs, finding that the key gene expression pathways of differentiated hPSC-PCs most closely matched those of late juvenile mouse PCs (P21). Comparative bioinformatics identified classical PC gene signatures as well as novel mitochondrial and autophagy gene pathways during the differentiation of both mouse and human PCs. In addition, we identified genes expressed in hPSC-PCs but not mouse PCs and confirmed protein expression of a novel human PC gene, CD40LG, expressed in both hPSC-PCs and native human cerebellar tissue. This study therefore provides a direct comparison of hPSC-PC and mouse PC gene expression and a robust method for generating differentiated hPSC-PCs with human-specific gene expression for modeling developmental and degenerative cerebellar disorders.
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Li, Yajuan, Mei Yan, Yong Du, Soyoun Min, Chandra Mohan, and Quanzhen Li. "The anti-oxidative role of glutathione s-transferase mu 2 in anti-GBM induced glomerulonephritis by inhibiting inflammation and oxidative stress (P5121)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 137.2. http://dx.doi.org/10.4049/jimmunol.190.supp.137.2.
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Abstract Oxidative stress is a common manifestation in chronic inflammation and closely associated with autoimmune diseases. Impaired balance between oxidative stress and antioxidant systems exhibits an important impact on pathogenesis of immune-mediated nephritis. Using anti-GBM induced nephritis mouse model, we have identified a group of redox related genes dysregulated in mouse kidney upon anti-GBM antibody challenge. In this study, we investigated the anti-oxidative effect of glutathione s-transferase mu 2 (Gstm2) on immune-mediated nephritis. Human GSTM2 gene was transduced into mesenchymal stem cell (MSC) and hGSTM2-MSCs were injected to anti-GBM antibody challenged 129/svj mice. Mouse blood urea nitrogen (BUN) and proteinuria were measured to evaluate renal function change and renal histopathological changes were appraised. We found the Gstm2 could alleviate the renal inflammatory damage by suppressing expression of inflammatory chemokines, CCL2, IL1β and IL6 to reduce macrophage and T lymphocyte infiltration. Gstm2 improved renal function by reducing BUN and proteinuria. Moreover, hGSTM2-MSCs significantly reduced the apoptosis of tubular cell by regulating the expression of anti-apoptotic genes (BCL2 and CD40LG) and hGSTM2-MSCs resisted oxidative stress by increasing the expression of catalase and glutathione peroxidase 1. In summary, Gstm2 exhibits protective effect on immune-mediated nephritis by inhibiting inflammatory damage and oxidative stress during inflammatory process.
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De Maio, Diego Javier Prado, Bitha Narayanan, James La Porta, Usha Ganapathi, Ping Xie, and Lori R. Covey. "Activation-dependent post-transcriptional regulation of CD40L mediates B cell development and survival in germinal centers." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 63.03. http://dx.doi.org/10.4049/jimmunol.206.supp.63.03.
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Abstract We have described a posttranscriptional pathway of induced mRNA stability that occurs at late times of T cell activation and is engaged by the binding of a polypyrimidine tract-binding protein (PTBP1) complex to the 3′UTR of the CD40L transcript. We explored the in vivo role of this pathway by generating a mouse bearing a deletion of the CD40L stability element (termed CD40LΔ5) and found that Tfh cells harboring the stability defect expressed approximately 60% of WT CD40L. Importantly, this decrease in CD40L corresponded to a poorly elaborated germinal center (GC) response which included significantly decreased levels of switched antibodies, antibody-secreting cells, GL7+ B cells and differentiated GC B cell subsets. In contrast, there was little difference in either somatic hypermutation or affinity maturation between B cells from WT compared to CD40LD5 mice. Notably, both the number and percentage of early memory B cells and plasmablasts were significantly decreased indicating that CD40L expression linked to mRNA stability was critical for B cell differentiation. To understand the impact of this stability pathway on gene expression, CD19+ B cells from CD40LD5 immunized mice were transcriptionally profiled using RNAseq and pathways associated with cell survival and proliferation were downregulated and apoptotic pathways upregulated compared to WT B cells. Importantly, the level of AID mRNA was unchanged whereas c-myc expression was significantly reduced in GL7+ B cells. Together these findings reveal that the CD40L stability element plays a critical role in regulating CD40L expression in Tfh cells, which in turn supports the optimal proliferation and cell survival of high affinity GC B cells and the differentiation of B cell subsets.
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Kaur, Sukhbir, Duha Awad, Richard P. Finney, Thomas J. Meyer, Satya P. Singh, Margaret C. Cam, Baktiar O. Karim, Andrew C. Warner, and David D. Roberts. "CD47-Dependent Regulation of Immune Checkpoint Gene Expression and MYCN mRNA Splicing in Murine CD8 and Jurkat T Cells." International Journal of Molecular Sciences 24, no. 3 (January 30, 2023): 2612. http://dx.doi.org/10.3390/ijms24032612.
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Elevated expression of CD47 in some cancers is associated with poor survival related to its function as an innate immune checkpoint when expressed on tumor cells. In contrast, elevated CD47 expression in cutaneous melanomas is associated with improved survival. Previous studies implicated protective functions of CD47 expressed by immune cells in the melanoma tumor microenvironment. RNA sequencing analysis of responses induced by CD3 and CD28 engagement on wild type and CD47-deficient Jurkat T lymphoblast cells identified additional regulators of T cell function that were also CD47-dependent in mouse CD8 T cells. MYCN mRNA expression was upregulated in CD47-deficient cells but downregulated in CD47-deficient cells following activation. CD47 also regulated alternative splicing that produces two N-MYC isoforms. The CD47 ligand thrombospondin-1 inhibited expression of these MYCN mRNA isoforms, as well as induction of the oncogenic decoy MYCN opposite strand (MYCNOS) RNA during T cell activation. Analysis of mRNA expression data for melanomas in The Cancer Genome Atlas identified a significant coexpression of MYCN with CD47 and known regulators of CD8 T cell function. Thrombospondin-1 inhibited the induction of TIGIT, CD40LG, and MCL1 mRNAs following T cell activation in vitro. Increased mRNA expression of these T cell transcripts and MYCN in melanomas was associated with improved overall survival.
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Lin, S. C., and J. Stavnezer. "Activation of NF-kappaB/Rel by CD40 engagement induces the mouse germ line immunoglobulin Cgamma1 promoter." Molecular and Cellular Biology 16, no. 9 (September 1996): 4591–603. http://dx.doi.org/10.1128/mcb.16.9.4591.
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Interaction between CD40 on B cells and CD40 ligand (CD40L) on T cells has been shown to mediate T-cell contact help for B-cell proliferation, differentiation, and immunoglobulin isotype switching. It has recently been shown that cross-linking CD40 on mouse B cells induces germ line gamma1 and epsilon transcripts and that interleukin-4 synergizes with CD40 signaling to further induce these germ line transcripts. Germ line transcripts have been shown to be required for class switch recombination. Here we show that signaling via CD40 increases expression of a transiently transfected luciferase reporter plasmid driven by the germ line Cgamma1 promoter in M12.4.1 B-lymphoma cells. By linker-scanning mutation analysis of the promoter, we have identified a CD40-responsive region (CD40RR) which is able to confer inducibility by CD40L to a minimal c-fos promoter. The CD40RR contains three binding sites for NF-kappaB/Rel proteins which are each required for maximal induction of CD40RR activity by CD40L. Binding of the NF-kappaB/Rel proteins p50, p65, c-Rel, and RelB to the CD40RR is induced by CD40 signaling in M12.4.1 cells and in splenic B cells. Cotransfection of expression plasmids for p50 and p65 or p50 and RelB, but not c-Rel, into M12.4.1 cells transactivates the CD40RR and the germ line gamma1 promoter. These data demonstrate that NF-kappaB Rel proteins activated by CD40 ligation play an important role in induction of the germ line Cgamma1 promoter.
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Fujisawa, Manabu, Tran B. Nguyen, Yoshiaki Abe, Yasuhito Suehara, Kota Fukumoto, Sakurako Suma, Kensuke Usuki, et al. "Germinal Center B Cells Derived from TET2-Mutated Clonal Hematopoiesis Provide a Microenviromental Niche for Tumor Cells in Angioimmunoblastic T-Cell Lymphoma." Blood 138, Supplement 1 (November 5, 2021): 445. http://dx.doi.org/10.1182/blood-2021-149983.
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Abstract Background Angioimmunoblastic T-cell lymphoma (AITL) is proposed to be initiated by age-related clonal hematopoiesis (ACH) with TET2mutations, whereas the G17V RHOA mutation in TET2-mutated immature cells facilitates development of T follicular helper (T FH)-like tumor cells. Notably, we and others have reported that immune cells derived from ACH with TET2 mutations infiltrate AITL tissues. However, how ACH-derived immune cells function as a microenvironmental niche in AITL remains largely unknown. Objective To elucidate the role of TET2-mutated immune cells in AITL tumorigenesis. Methods The G17V RHOA transgenic mice were crossed with mice lacking Tet2 in all blood cells (Mx-Crex Tet2f/f, A) and in T cells (Cd4-Crex Tet2f/f, B), respectively. Single-cell RNA sequencing (Sc-seq) was performed on >60,000 cells from AITL in mice (AITLm, n=2) and human (AITLh, n=5), and their controls to reveal the immune profiles. We used Seurat and Monocle3 pipelines for analysis of Sc-seq. Whole genome bisulfite sequencing (WGBS) was used to analyze the methylome of germinal center B (GCB) cells in AITLm and control. Results AITLm occurred only in A, but not in B. Then, we intraperitoneally transplanted Cd4 + tumor-containing cells together with various lineages of immune cells sorted from AITLm into nude mice. AITLm developed only when B-lineage cells were cotransplanted with Cd4 + tumor-containing cells. Unsupervised clustering of the Sc-seq data identified 6 T-, 6 B- and 3 myeloid clusters in AITLm. B-cell clusters were annotated into naïve B-, memory B-, GCB-, and plasma clusters along the B-cell differentiation through Geneset variable analysis (GSVA) and trajectory analysis. We found that the aberrant GCB clusters, simultaneously exhibiting DZ-like proliferation markers (Aicda and Mki67) and LZ-like activation markers (Cd40, Cd83) were markedly expanded in AITLm. Geneset Enrichment Analysis (GSEA) revealed that MYC targets and other signaling pathways involved in cell proliferation were highly enriched in the GCB clusters in AITLm. WGBS showed that the number of hypermethylated regions (HyperDMRs) was markedly higher than that of hypomethylated regions (HypoDMRs) at all the regions; promoters, exons, introns, untranslated and intergenic regions. Among HyperDMRs, Atp13a2, Pdzd2, Rapgef4, Irf4 and Egr3 expressions were downregulated in the GCB clusters of Sc-seq in AITLm. Remarkably, the number of BCR clones in GCB of AITLm were significantly less than those in controls. In addition, in AITLm mice, the number of somatic mutations in GCB cells was significantly higher than that in T FH-like tumor cells. Remarkably, we detected unique core histone mutations in the GCB cells of AITLm, including the recurrent p.Ser87Asn Histone3 mutations. Next, In silico network analysis using Sc-seq data between GCB and T FH-like clusters identified that 11 interactions, including Cd40-Cd40lg were significantly enhanced in AITLm compared to controls. Flowcytomeric analysis revealed that cell-surface expression of Cd40 were significantly higher in the GCB cells of AITLm than those of control. Pathologically, the follicular structure was disrupted in AITLm. Consequently, Cd40lg +Cd4 +tumor cells and Cd40 +Cd19 + cells were both diffusely distributed and sometimes localized adjacent to each other. Finally, administration of an anti-Cd40lg antibody prolonged the survival of nude mice transplanted with AITLm. In AITLh with TET2 mutations, unsupervised clustering of Sc-seq identified T-, B-, and myeloid-cell clusters and a cluster characterized by proliferative markers. In B-lineage cells, 9 clusters were re-clustered and annotated to naïve or memory B-, GCB- and plasmablast clusters under the same manner of mouse data. Gene ontology analysis from differential expression genes in each cluster showed that the GCB- and CD40-related genesets were enriched not only in the GCB cluster but also in the naive to memory B clusters. Furthermore, the AITL-B-specific geneset, which referred from genes (CD40, CD83, AICDA, MKI67) highly expressed in the GCB cluster in AITLm was enriched not only in the GCB cluster, but also in the naive to memory B clusters in AITLh. Conclusion This study suggests a new concept that ACH-derived GCB cells with TET2 mutations can undergo independent clonal evolution and function as microenvironmental cells to support tumorigenesis in AITL via the CD40-CD40LG axis. Disclosures Usuki: Astellas Pharma Inc.: Research Funding, Speakers Bureau; AbbVie GK: Research Funding, Speakers Bureau; Gilead Sciences, Inc.: Research Funding; SymBio Pharmaceuticals Ltd.: Research Funding, Speakers Bureau; Daiichi Sankyo Co., Ltd.: Research Funding, Speakers Bureau; Sumitomo-Dainippon Pharma Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Novartis Pharma K.K.: Research Funding, Speakers Bureau; Ono Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Janssen Pharmaceutical K.K.: Research Funding; Celgene K.K.: Research Funding, Speakers Bureau; Takeda Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Nippon-Boehringer-Ingelheim Co., Ltd.: Research Funding; Mundipharma K.K.: Research Funding; Amgen-Astellas Biopharma K.K.: Research Funding; Nippon-Shinyaku Co., Ltd.: Research Funding, Speakers Bureau; Kyowa-Kirin Co., Ltd.: Research Funding, Speakers Bureau; Pfizer Japan Inc.: Research Funding, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Research Funding, Speakers Bureau; Eisai Co., Ltd.: Speakers Bureau; MSD K.K.: Research Funding, Speakers Bureau; PharmaEssentia Japan KK: Research Funding, Speakers Bureau; Yakult Honsha Co., Ltd.: Research Funding, Speakers Bureau; Bristol-Myers-Squibb K.K.: Research Funding, Speakers Bureau; Apellis Pharmaceuticals, Inc.: Research Funding; Incyte Biosciences Japan G.K.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Sanofi K.K.: Speakers Bureau; Amgen K.K.: Research Funding.
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Narayanan, Bitha, Diego Prado De Maio, Katie Voskoboynik, James La Porta, Ping Xie, and Lori R. Covey. "Activation-dependent Posttranscriptional Regulation of CD40L is Required for an Optimal Germinal Center (GC) response." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 186.16. http://dx.doi.org/10.4049/jimmunol.202.supp.186.16.
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Abstract We have previously shown that regulation of CD40L occurs in part through a posttranscriptional mechanism of activation-induced mRNA stability. This pathway is engaged at extended times of activation and is mediated by the binding of a polypyrimidine tract binding protein (PTBP1) complex to the 3′UTR of the CD40L mRNA. This process leads to sustained expression of CD40L on CD4 T cells at a time when overall transcript levels are low. To assess the role of this regulatory pathway on an ongoing immune response we engineered a novel knock-in mouse (CD40LΔ5) that lacked the PTBP1 stability element and challenged mice with NP-KLH and SRBCs. Examination of splenic subsets prior to immunization revealed no difference in number or ratio between mutant and WT mice. However, after immunization there were significant decreases in T-dependent antibodies (Abs) and these differences were exacerbated with secondary challenge. In contrast, there were no differences in Ab response to a T-independent antigen. In total, CD40LΔ5 mice displayed significant changes in multiple aspects of the GC response including reduced levels of plasma cells, memory cells and GL7+ B cells. However, there were no observed differences in the number of Tfh cells between mutant and WT mice. Evaluation of GC structure in splenic sections revealed highly disordered GCs in CD40LΔ5 compared to WT mice at 8 days following immunization with SRBCs. Therefore, we hypothesize that the T cell activation-induced stabilization of the CD40L message and the subsequent surface expression of the protein is critical for development of a robust GC response and this occurs on one level by directly impacting the structural architecture of the GC.
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Piguet, Pierre Francois, Chen Da Kan, Christian Vesin, Anne Rochat, Yves Donati, and Constance Barazzone. "Role of CD40-CD40L in Mouse Severe Malaria." American Journal of Pathology 159, no. 2 (August 2001): 733–42. http://dx.doi.org/10.1016/s0002-9440(10)61744-0.
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De Maio, Diego Javier Prado, Bitha Narayanan, James La Porta, Ping Xie, and Lori R. Covey. "Activation-dependent post-transcriptional regulation of CD40L mediates B cell development and survival in germinal centers." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 151.6. http://dx.doi.org/10.4049/jimmunol.204.supp.151.6.
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Abstract We have previously described a post-transcriptional pathway of induced mRNA stability that occurs at late times of T cell activation and is engaged by the binding of polypyrimidine tract-binding protein (PTBP1) complex to the 3′ UTR of the CD40L transcript. We recently explored the in vivo role of this pathway by generating a genetically modified mouse (CD40LΔ5) bearing a deletion of the PTBP1 stability element. We found that the CD40LΔ5 mice display a dysfunctional germinal center (GC) response including significantly decreased levels of isotype switched antibodies, antibody-secreting cells, memory B cells and GL7+ GC B cells. To extend our earlier findings we measured affinity maturation of antibodies in response to the hapten NP and found a loss of high affinity binding that corresponded to reduced numbers of targeted VH mutations known to be associated with high affinity binding. However, there were no discernible differences in the overall number of mutations across the VH segment, suggesting that the CD40LΔ5 pathway may have a greater effect on the selection and/or expansion of high-affinity B cells rather than on the somatic hypermutation (SHM) in general. To identify how the CD40L mRNA stability pathway impacted B cells during an immune response, CD19+ B cells from immunized mice were transcriptionally profiled using RNAseq. Expression of genes associated with cell survival and proliferation were found to be down-regulated and apoptotic genes up-regulated in CD40LΔ5 B cells compared to WT cells. Together these finding are consistent with the Δ5 stability element playing a critical role in the proliferation and cell survival of high affinity GC B cells through a pathway of enhanced expression of CD40L in CD4 T cells.
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Keam, Simon, Heloise Halse, ThuNgoc Nguyen, Minyu Wang, Nicolas Van Kooten Losio, Catherine Mitchell, Franco Caramia, et al. "580 High dose-rate brachytherapy of localized prostate cancer converts tumors from cold to hot." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A614—A615. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0580.
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BackgroundProstate cancer is frequently cured with high dose-rate brachytherapy (HDRBT) radiation as a front-line treatment. Although considered to be an immune-excluded tissue, immune responses to radiation are implicated in driving tumour-eradication in prostate cancer.1 This has not been proven, and yet is used as the rationale for clinical trials combining radiation and immunotherapies.2 We hypothesise that there is a predictable relationship between radiation and the immune responses in prostate cancer that could be used to provide sound rationale for specific immune interventions in solid tumours that are made possible by radiation therapy.MethodsWe present here new results stemming from our recently published immunoprofiling study of world-unique pre- and post-radiation tissues from 24 prostate cancer patients (figure 1A), RadBank cohort).3 These samples were assessed using immune cell multiplex IHC, gene expression profiling, digital spatial profiling (DSP) and computational analysis of cell distribution.ResultsThis study unequivocally revealed that high dose-rate radiation converts predominately ‘cold’ prostate tumour tissue to a more activated ‘hot’ state comprised of two sub-types (high and a less activated intermediate state). These changes were evident in increased tumour inflammation gene signatures and immune checkpoint expression, immune cell composition changes, and alterations in spatial interactions. However, as 20% of the patients did not respond, we also explored pre-treatment gene signatures of patient responses to radiation – identifying potential mechanisms that prime tissues to respond more favourably. Most recently, we have explored three other important facets of the immune response to HDRBT: (i) putative differential drivers of high and intermediate responses (figure 1B), (ii) TCR clonality changes (figure 1C), and (iii) the influence of clinical features (e.g. Gleason grade) and treatment (e.g. androgen deprivation) (figure 1D). Differential expression analysis has identified key molecules (e.g. CD40LG and Lck expression) which are associated with higher activation responses. TCR sequencing of pre- and post-HDRBT tissue and peripheral circulating cells is also suggestive of engagement of the adaptive immune system and the emergence of tumor-specific T cells. Finally, multivariate analysis has also revealed that higher grade tumours exhibit higher basal levels of activation and IC expression – making them less sensitive to immune activation by HDRBT.Abstract 580 Figure 1The effect of prostate brachytherapy on immune contexts(A) Study of immune response in 24 patients treated with HDRBT at Peter MacCallum Cancer Center ((DOI:10.1136/jitc2020-000792). Examples of new insights including (B) molecules associated with higher activation levels (e.g. Lck and CD40LG/CD154), (C) changes in T cell receptor dominance and diversity in tissue and peripheral circulation, and (D) effects of clinical attributes on immune modulators (e.g. TGFbeta) and TIS activation states.ConclusionsWe have begun to resolve clear patient and clinical classifiers based on immune responses to radiation, and identified patient groups likely to benefit from immune therapy alongside radiation. Importantly, these classifications are associated with baseline gene expression profiles that may be used for pre-clinical stratification and more sophisticated treatment paradigms.Ethics ApprovalAll participants provided consent covering tissue research as part of a prospective tissue collection study for prostate radiobiology research, approved by the Human Research Ethics Committee at the Peter MacCallum Cancer Centre (PMCC; HREC approvals 10/68, 13/167, 18/204).ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.ReferencesDudzinski SO, et al., Combination immunotherapy and radiotherapy causes an abscopal treatment response in a mouse model of castration resistant prostate cancer. J Immunother Cancer 2019. 7(1): p. 218.Kwon E.D., et al., Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol 2014;15(7): p. 700–12.Keam SP, et al., High dose-rate brachytherapy of localized prostate cancer converts tumors from cold to hot. J Immunother Cancer 2020;8(1).
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De Maio, Diego Javier Prado, Usha Ganapathi, and Lori Covey. "Decreased CD40L through disrupted transcriptional stability affects the autoimmune response in a sex-dependent manner in a GVHD model of SLE." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 112.23. http://dx.doi.org/10.4049/jimmunol.208.supp.112.23.
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Abstract Increased levels of CD40L have been observed on CD4 T cells of patients with systemic lupus erythematosus (SLE) and in several murine models of lupus-like disease. Notably, elevated/prolonged expression of CD40L corresponds to the expansion and survival of autoreactive B cells. However, targeting CD40L as a potential therapeutic has been challenging due to the development of off-target events. We have developed a unique mouse model termed CD40LΔ5 (Δ5) which lacks a stability element in the 3’ UTR of the CD40L message and upon immunization, shows decreased CD40L expression on Tfh cells leading to both reduced GC B cell survival and a critically disproportional loss of pre-memory B cells. Using our Δ5 model, we sought to determine whether reduced CD40L could substantially alter the development of disease in an adoptive transfer model of lupus based upon MHC II incompatibility. B6 WT mice were engrafted with CD4 T cells from bm12-WT or bm12-Δ5 mice and analyzed for splenic lymphocyte subsets. In mice that received Δ5 T cells, total CD4 and CD8 subsets were unchanged compared to mice receiving WT cells, however, there was an increase and decrease of Tfh cells in male and female mice, respectively. This was confirmed by a corresponding change in Tfh proliferation as measured by staining for Ki67. Total CD19 B cells were increased in male mice receiving D5 T cells. Finally, intracellular staining of T cell cytokines was different in male and female mice receiving the Δ5 T cells as was the distribution of GC B cell subsets, including pre-memory B cells. Together our results suggest that limiting CD40L in T cells at an early stage of bm12-induced lupus has a significant effect on the maturation of GC subsets that is closely aligned with the sex of the WT recipient mice. Supported by AAI Careers in Immunology Fellowship 2019-2020
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Saadi, Fareeha, Debanjana Chakravarty, Saurav Kumar, Mithila Kamble, Bhaskar Saha, Kenneth S. Shindler, and Jayasri Das Sarma. "CD40L protects against mouse hepatitis virus-induced neuroinflammatory demyelination." PLOS Pathogens 17, no. 12 (December 13, 2021): e1010059. http://dx.doi.org/10.1371/journal.ppat.1010059.
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Neurotropic mouse hepatitis virus (MHV-A59/RSA59) infection in mice induces acute neuroinflammation due to direct neural cell dystrophy, which proceeds with demyelination with or without axonal loss, the pathological hallmarks of human neurological disease, Multiple sclerosis (MS). Recent studies in the RSA59-induced neuroinflammation model of MS showed a protective role of CNS-infiltrating CD4+ T cells compared to their pathogenic role in the autoimmune model. The current study further investigated the molecular nexus between CD4+ T cell-expressed CD40Ligand and microglia/macrophage-expressed CD40 using CD40L-/- mice. Results demonstrate CD40L expression in the CNS is modulated upon RSA59 infection. We show evidence that CD40L-/- mice are more susceptible to RSA59 induced disease due to reduced microglia/macrophage activation and significantly dampened effector CD4+ T recruitment to the CNS on day 10 p.i. Additionally, CD40L-/- mice exhibited severe demyelination mediated by phagocytic microglia/macrophages, axonal loss, and persistent poliomyelitis during chronic infection, indicating CD40-CD40L as host-protective against RSA59-induced demyelination. This suggests a novel target in designing prophylaxis for virus-induced demyelination and axonal degeneration, in contrast to immunosuppression which holds only for autoimmune mechanisms of inflammatory demyelination.
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Tay, Neil Q., Debbie C. P. Lee, Yen Leong Chua, Nayana Prabhu, and David Michael Kemeny. "CD40L signaling from CD8+ T cells confers protection against influenza infection." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 56.8. http://dx.doi.org/10.4049/jimmunol.196.supp.56.8.
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Abstract CD40L is a principal mediator of a large range of humoral and cellular responses and CD40L-mediated licensing of dendritic cells is known to be necessary for the generation of robust effector and memory CD8+ T cell responses. Although the effects of CD40L when expressed on CD4+ T cells are well studied, its role when expressed on CD8+ T cells remain unclear. We have previously reported that CD40L signaling mediates the induction of IL-12 p70 production in dendritic cells when expressed by CD8+ T cells. However, the role and importance of this mechanism in CD8+ T cell responses during an infection are not known. To investigate the function of CD40L when expressed on CD8+ T cells in an in vivo mouse model, we crossed OT-I CD8+ T cell receptor transgenic mice with CD40L−/− mice to generate OVA-specific CD8+ T cells that are unable to expressed CD40L. By transferring CD8+ T cells from these mice into CD40L-competent mice and using a strain of influenza that expresses the OVA epitope recognized by OT-I CD8+ T cells, we were able to create an influenza mouse model where CD40L signaling is absent only on the responding CD8+ T cells. Our analysis indicates that CD40L signaling by CD8+ T cells confers protection against influenza infection and that this is likely dependent on the ability of CD8+ T cells to induce IL-12 p70 production in a CD40L-dependent manner.
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Iciek, L. A., S. A. Delphin, and J. Stavnezer. "CD40 cross-linking induces Ig epsilon germline transcripts in B cells via activation of NF-kappaB: synergy with IL-4 induction." Journal of Immunology 158, no. 10 (May 15, 1997): 4769–79. http://dx.doi.org/10.4049/jimmunol.158.10.4769.
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Abstract Transcription of unrearranged (germline) Ig heavy chain C region (C(H)) genes is required before Ab class switch recombination. Although the cytokine IL-4 is well known to induce transcription of unrearranged C epsilon and C gamma1 genes, it has been shown recently that CD40 signaling also induces these transcripts in mouse B cells. We report in this study that treatment of mouse M12.4.1 B lymphoma cells with soluble CD40 ligand (CD40L)-CD8alpha fusion protein modestly induces the promoter for germline epsilon transcripts, and that this induction synergizes with IL-4. CD40L induces binding of nuclear factor (NF)-kappaB/Rel proteins to two tandem kappaB sites located immediately 3' to the IL-4-responsive region of the mouse germline epsilon promoter. The epsilon-124/-56 promoter segment containing the IL-4 response region and the two kappaB sites is sufficient to transfer CD40L and IL-4 inducibility to a minimal c-fos promoter when transiently transfected into M12.4.1 cells. Mutation of the two kappaB sites eliminates induction by CD40L or by IL-4, and treatment of M12.4.1 cells with inhibitors of NF-kappaB activation prevents induction of endogenous germline epsilon transcripts in M12.4.1 cells. In addition to the NF-kappaB/Rel complexes induced by CD40L, two nuclear complexes, each which contain both STAT6 and NF-kappaB/Rel proteins, are induced in splenic B cells by a combination of CD40L and IL-4, and bind to the CD40L/IL-4-responsive region of the germline epsilon promoter. The presence of these complexes may explain the synergistic induction of transcription by CD40L and IL-4 mediated through this promoter segment.
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Aslam, Mohammad, Yusuke Kishi, and Takeshi Tsubata. "Excess CD40L does not rescue anti-DNA B cells from clonal anergy." F1000Research 2 (October 17, 2013): 218. http://dx.doi.org/10.12688/f1000research.2-218.v1.
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CD40L, a member of the tumor necrosis factor (TNF) ligand family, is overexpressed in patients with systemic lupus erythematosus and in lupus mouse models. Previously, we demonstrated that B cells producing pathogenic anti-Sm/RNP antibodies are deleted in the splenic marginal zone (MZ), and that MZ deletion of these self-reactive B cells is reversed by excess CD40L, leading to autoantibody production. To address whether excess CD40L also perturbs clonal anergy, another self-tolerance mechanism of B cells whereby B cells are functionally inactivated and excluded from follicles in the peripheral lymphoid tissue, we crossed CD40L-transgenic mice with the anti-DNA H chain transgenic mouse line 3H9, in which Ig λ1+ anti-DNA B cells are anergized. However, the percentage and localization of Ig λ1+ B cells in CD40L/3H9 double transgenic mice were no different from those in 3H9 mice. This result indicates that excess CD40L does not perturb clonal anergy, including follicular exclusion. Thus, MZ deletion is distinct from clonal anergy, and is more liable to tolerance break.
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Aslam, Mohammad, Yusuke Kishi, and Takeshi Tsubata. "Excess CD40L does not rescue anti-DNA B cells from clonal anergy." F1000Research 2 (January 15, 2014): 218. http://dx.doi.org/10.12688/f1000research.2-218.v2.
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CD40L, a member of the tumor necrosis factor (TNF) ligand family, is overexpressed in patients with systemic lupus erythematosus and in lupus mouse models. Previously, we demonstrated that B cells producing pathogenic anti-Sm/RNP antibodies are deleted in the splenic marginal zone (MZ), and that MZ deletion of these self-reactive B cells is reversed by excess CD40L, leading to autoantibody production. To address whether excess CD40L also perturbs clonal anergy, another self-tolerance mechanism of B cells whereby B cells are functionally inactivated and excluded from follicles in the peripheral lymphoid tissue, we crossed CD40L-transgenic mice with the anti-DNA H chain transgenic mouse line 3H9, in which Ig λ1+ anti-DNA B cells are anergized. However, the percentage and localization of Ig λ1+ B cells in CD40L/3H9 double transgenic mice were no different from those in 3H9 mice. This result indicates that excess CD40L does not perturb clonal anergy, including follicular exclusion. Thus, MZ deletion is distinct from clonal anergy, and is more liable to tolerance break.
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Chen, F. A., S. S. Williams, W. C. Fanslow, and R. B. Bankert. "Human antibody response in human peripheral blood leukocyte/severe combined immunodeficient chimeric model is dependent on B and T cell costimulation via CD40/CD40 ligand." Journal of Immunology 155, no. 6 (September 15, 1995): 2833–40. http://dx.doi.org/10.4049/jimmunol.155.6.2833.
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Abstract We have used a human/severe combined immunodeficient (SCID) mouse chimeric model (in which human PBLs are engrafted into SCID mice) to investigate in vivo the role of the CD40/CD40 ligand (CD40L) interaction in the generation of humoral immunity by engrafted human cells. It is established in this work that the thymic dependent, multiclonal, humoral immune response of human lymphocytes to mouse erythrocyte protein Ags is inhibited significantly when CD40/CD40L ligation is prevented in vivo. Suppression of the response was observed with administration of neutralizing Abs specific for either CD40 or CD40L, or with the soluble fusion protein human CD40-Fc. Human anti-mouse erythrocyte Abs and the total human Ig levels in the sera of the SCID mice were suppressed for up to 10 wk when the neutralizing agents were administered at the time of human leukocyte engraftment, i.e., coincident with Ag stimulation, and subsequently at 2 and 4 days after Ag stimulation. These results are the first to demonstrate the ability of CD40/CD40L blocking agents to inhibit the human Ag-specific humoral immune response in vivo, and they sustain the notion that these blocking agents may be utilized clinically to eliminate immune responses associated with autoimmunity or allergy. In addition to confirming the importance of the CD40/CD40L interaction of T and B cells in vivo, it is established in this work that the mouse erythrocyte-specific humoral immune response of the lymphocytes in the human PBL/SCID mouse model is a bona fide T cell-dependent response, and that this is a viable model with which to study human lymphocyte activation in vivo. These results also suggest that the costimulatory activation of human B and T cells is not dependent on the microenvironment of the germinal centers.
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Wang, Ruikun, Jingru Chen, Wei Wang, Zhuoqian Zhao, Haoran Wang, Shiyu Liu, Fan Li, et al. "CD40L-armed oncolytic herpes simplex virus suppresses pancreatic ductal adenocarcinoma by facilitating the tumor microenvironment favorable to cytotoxic T cell response in the syngeneic mouse model." Journal for ImmunoTherapy of Cancer 10, no. 1 (January 2022): e003809. http://dx.doi.org/10.1136/jitc-2021-003809.
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BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the most malignant cancers worldwide. Despite the promising outcome of immune checkpoint inhibitors and agonist antibody therapies in different malignancies, PDAC exhibits high resistance due to its immunosuppressive tumor microenvironment (TME). Ameliorating the TME is thus a rational strategy for PDAC therapy. The intratumoral application of oncolytic herpes simplex virus-1 (oHSV) upregulates pro-inflammatory macrophages and lymphocytes in TME, and enhances the responsiveness of PDAC to immunotherapy. However, the antitumor activity of oHSV remains to be maximized. The aim of this study is to investigate the effect of the CD40L armed oHSV on the tumor immune microenvironment, and ultimately prolong the survival of the PDAC mouse model.MethodsThe membrane-bound form of murine CD40L was engineered into oHSV by CRISPR/Cas9-based gene editing. oHSV-CD40L induced cytopathic effect and immunogenic cell death were determined by microscopy and flow cytometry. The expression and function of oHSV-CD40L was assessed by reporter cell assay. The oHSV-CD40L was administrated intratumorally to the immune competent syngeneic PDAC mouse model, and the leukocytes in TME and tumor-draining lymph node were analyzed by multicolor flow cytometry. Intratumoral cytokines were determined by ELISA.ResultsIntratumoral application of oHSV-CD40L efficiently restrained the tumor growth and prolonged the survival of the PDAC mouse model. In TME, oHSV-CD40L-treated tumor accommodated more maturated dendritic cells (DCs), which in turn activated T helper 1 and cytotoxic CD8+ T cells in an interferon-γ-dependent and interleukin-12-dependent manner. In contrast, the regulatory T cells were significantly reduced in TME by oHSV-CD40L treatment. Repeated dosing and combinational therapy extended the lifespan of PDAC mice.ConclusionCD40L-armed oncolytic therapy endues TME with increased DCs maturation and DC-dependent activation of cytotoxic T cells, and significantly prolongs the survival of the model mice. This study may lead to the understanding and development of oHSV-CD40L as a therapy for PDAC in synergy with immune checkpoint blockade.
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Rudqvist, Nils, Claire Lhuillier, Maud Charpentier, Erik Wennerberg, Sheila Spada, Caroline Sheridan, Xi Kathy Zhou, et al. "465 Radiotherapy and CTLA-4 blockade expand anti-tumor T cells differentiation states and cooperate with CD40 agonist to induce tumor rejection." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A494—A495. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0465.
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BackgroundRadiotherapy (RT) in combination with CTLA-4 inhibition (CTLA4i) can expand and activate T-cells to reject tumors in both mice and some patients with tumors unresponsive to CTLA4i alone.1 2 However, only a subset of patients achieves long-term control of metastatic disease. Similar responses to RT+CTLA4i are seen in the 4T1 mouse model of triple negative breast cancer (TNBC), making it an ideal model to interrogate the interaction between RT and CTLA4i, and identify barriers to its effectiveness.MethodsMice were inoculated in one or both flanks with 4T1 cells. In some experiments one tumor was removed for analysis before start of treatment with RT (3 × 8 Gy) and/or anti-CTLA-4 antibody (9H10, 3 × 200 ?g i.p.). The intratumoral T cell response was assessed using bulk and single cell RNA/TCR sequencing. The METABRIC dataset3 was used to associate gene expression signatures with patient survival. In some experiments, RT+CTLA4i was combined with PD-1, LAG-3, or CD40 Abs.ResultsRT, alone and with CTLA4i, increased the TCR repertoire clonality and activated T cells density in the tumors (figure 1A-G). In untreated tumors, Gzmb+Prf1+Lag3+Pd1+Cd8+ T cells (cluster 0) were most common. CTLA4i ‘unlocked’ Ifng+Cd40lg+ Cd4+ T cells (cluster 2) while RT favored expansion/persistence of Cd8+ T cell clusters. In tumors of mice treated with RT+CTLA4i activated Treg cells (cluster 1) were decreased and Ifng+Cd40lg+Cd4+ T cells (cluster 2) increased. Relatively among CD8+ T cells, Ifng+Tnf+Cd8+ (cluster 4) was expanded at the expense of cluster 0 (figure 2A-F). Gene signatures defining clusters 0, 2, and 4 were associated with improved survival in the METABRIC TNBC patient cohort using a multivariate model (figure 2G-H). In mice, AH1-tumor antigen-specific CD8+ T cells occupied different transcriptional states, with a shift to cluster 4 in mice treated with RT+CTLA4i (figure 2I), suggesting that multiple functional T cell states are required for tumor rejection. Based on the T cell phenotypes expanded by RT+CTLA4i, antibodies to PD-1, LAG-3, and CD40 were tested for the ability to enhance RT+CTLA4i therapy. Only CD40-agonist improved significantly tumor control (figure 3A-B).Abstract 465 Figure 1RT, alone and with CTLA4i, increased the TCR repertoire clonality and density of activated T cells in the tumors. (A) Design of the experiment enabling collection of pre- and post-treatment (pre-tx and post-tx) 4T1 tumor tissue that was analyzed using RNA- and TCR-sequencing. (B) Tumor growth curves. Statistical significance in tumor volume growth between groups was determined using 2-way repeated measures ANOVA between day 15–21 and t-test at day 21. (C) Shannon clonality of paired pre- and post-tx TCR repertoires. Pairwise and paired t-tests were used to evaluate statistical significance of differences between and within groups, respectively. (D) RNA-seq based gene expression heatmap of selected canonical T cell markers in post-tx tumors. (E) Linear regression between Cd3e and Cd4 or Cd8 gene expression in post-tx tumors. R2 and p indicate R-square and p-value for the models, respectively (F) Ingenuity Pathway Analysis Canonical Pathway and (G) Upstream Regulation analysis. Z-scores indicate predicted activation (> 2) or inhibition (< -2) of pathways and upstream regulators. (all panels) *, **, and ***, and #, ## and ### indicate p-values of pairwise and paired statistical tests, respectively. Tukey’s and Holm’s method for adjusting p-values corrected for multiple comparison was used for the ANOVA and t-tests, respectively. (Abbreviations) tx, treatment; RT, radiation therapy; CTLA4, CTLA-4 Ab therapy; TCR, T cell receptorAbstract 465 Figure 2RT+CTLA-4i increased tumor infiltration by Gzmb+Prf1+Lag3+Pd1+Cd8+, Ifng+Cd40lg+Cd4+, and Ifng+Tnf+Cd8+ T cells in 4T1 tumors. (A) Design of experiment enabling single cell analysis of T cells infiltrating 4T1 tumors. (B) Based on gene expression levels, the T cells were divided into 17 clusters (indicated by colors) and visualized in 2D using UMAP dimensionality reduction algorithm. (C) Gene expression levels of selected high-level T cell markers. (D) Table with main phenotype, key genes representative for each cluster, and the distribution of T cells from each condition falling into the different clusters. (E) Proportion of Cd4+ and Cd8+ T cells for the different treatment groups. (F) The expression of cluster-specific gene signatures in bulk 4T1 tumors for clusters 0, 2, and 4. (G) Survival curves and (H) multivariate analysis of the association between survival and enrichment of the gene signatures of clusters 0, 2, and 4. (I) The positioning of the all AH1-dextramer+ Cd8+T cell clones within the UMAP plot. Color annotate cluster. (Abbreviations) tx, treatment; RT, radiation therapy; Untr., untreated; CTLA4, CTLA-4 Ab; TCR CDR3, T cell receptor complementary determining region 3; UMAP, Uniform Manifold Approximation and Projection for dimension reduction; AH1, tumor antigen in 4T1 tumors; SPSYVYHQF peptide derived from gp70 and restricted to H2-LdAbstract 465 Figure 3Agonistic CD40 treatment improves RT+CTLA-4 therapy. Individual tumor growth curves for untreated, RT+CTLA-4, or RT+CTLA-4+CD40 treated mice. Color annotate group. *, **, ***, and **** indicate p-values < 0.05, 0.01, 0.001, and 0.0001, respectively, calculated using a linear mixed-effects model. (A) and (B) represent two individual experiments. (Abbreviations) RT, radiation therapy; CTLA4, CTLA-4 Ab; CD40, anti-CD40 Ab; mm3, cubic millimeter; d, daysConclusionsAltogether, these results revealed that RT and CTLA4i have complementary effects and besides driving T cells into tumors shape CD4 and CD8 T cell functional differentiation towards subsets that are associated with improved survival in patients. Unexpectedly, inhibition of checkpoint receptors expressed by a large CD8 T cells cluster did not further improve responses to RT+CTLA4i, whereas agonistic CD40 therapy did, suggesting new therapeutic strategies.AcknowledgementsGrant support: R01CA198533ReferencesK, Ferrari de Andrade L, Wucherpfennig KW, Heguy A, Imai N, Gnjatic S, Emerson RO, Zhou XK, Zhang T, Chachoua A, Demaria S. Radiotherapy induces responses of lung cancer to CTLA-4 blockade. Nat Med 2018;24(12):1845–51.Rudqvist NP, Pilones KA, Lhuillier C, Wennerberg E, Sidhom JW, Emerson RO, Robins HS, Schneck J, Formenti SC, Demaria S. Radiotherapy and CTLA-4 Blockade Shape the TCR Repertoire of Tumor-Infiltrating T Cells. Cancer Immunol Res 2018;6(2):139–50.Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, Speed D, Lynch AG, Samarajiwa S, Yuan Y, Graf S, Ha G, Haffari G, Bashashati A, Russell R, McKinney S, Group M, Langerod A, Green A, Provenzano E, Wishart G, Pinder S, Watson P, Markowetz F, Murphy L, Ellis I, Purushotham A, Borresen-Dale AL, Brenton JD, Tavare S, Caldas C, Aparicio S. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 2012;486(7403):346–52.
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Sharma, Madhav D., Maria Leite de Moraes, Flora Zavala, Christiane Pontoux, and Martine Papiernik. "Induction and Inhibition of CD40-CD40 Ligand Interactions: A New Strategy Underlying Host-Virus Relationships." Journal of Immunology 161, no. 10 (November 15, 1998): 5357–65. http://dx.doi.org/10.4049/jimmunol.161.10.5357.
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Abstract Interaction between CD40 and the CD40 ligand (CD40L) is required for mouse mammary tumor virus (MMTV) propagation. We found that Fas was expressed on B cells and CD40L on a small subset of viral superantigen-cognate T cells 12 h after MMTV(SW) infection. CD40L and Fas were down-regulated after 24 h. All CD4 T cells then became resistant to anti-CD3-induced CD40L induction in vitro for 2 wk. Initiation of CD40L expression and its rapid shut-off was associated with IL-12 production and was controlled by IFN-γ and shedding of soluble CD40. These results suggest that a rapid, transient CD40-CD40L interaction involving a small number of cells is sufficient for MMTV propagation. Modulation of CD40L expression may be a major mechanism regulating the balance between viral propagation and host defenses, allowing mutual survival.
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Cheng, Wei, Fangfang Wang, Airan Feng, Xiaodan Li, and Wencheng Yu. "CXXC5 Attenuates Pulmonary Fibrosis in a Bleomycin-Induced Mouse Model and MLFs by Suppression of the CD40/CD40L Pathway." BioMed Research International 2020 (April 4, 2020): 1–15. http://dx.doi.org/10.1155/2020/7840652.
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Objective. To investigate the role of CXXC5 and the CD40/CD40L pathway in lung fibrosis. Methods. (1) We constructed mouse models of bleomycin-induced pulmonary fibrosis and transfected them with a CXXC5 overexpression vector to evaluate the severity of pulmonary fibrosis. (2) Mouse lung fibroblast (MLF) models stably overexpressed or knockout of CXXC5 vector were constructed. After transforming growth factor-β1 (TGF-β1) stimulation, we examined the proliferation and apoptosis of the MLF model and evaluated the expression of mesenchymal markers and the CXXC5/CD40/CD40L pathway. Results. (1) Compared with other groups, the overexpressed CXXC5 group had less alveolar structure destruction, thinner alveolar septum, and lower Ashcroft score. (2) In bleomycin-induced mice, the expression of CD40 and CD40L increased at both transcriptional and protein levels, and the same changes were observed in α-smooth muscle actin (α-SMA) and collagen type I (Colla I). After upregulation of CXXC5, the increase in CD40, CD40L, α-SMA, and Colla I was attenuated. (3) Stimulated with TGF-β1, MLF proliferation was activated, apoptosis was suppressed, and the expression of CD40, CD40L, α-SMA, and Colla I was increased at both transcriptional and protein levels. After upregulation of CXXC5, these changes were attenuated. Conclusion. CXXC5 inhibits pulmonary fibrosis and transformation to myofibroblasts by negative feedback regulation of the CD40/CD40L pathway.
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Kato, T., R. Hakamada, H. Yamane, and H. Nariuchi. "Induction of IL-12 p40 messenger RNA expression and IL-12 production of macrophages via CD40-CD40 ligand interaction." Journal of Immunology 156, no. 10 (May 15, 1996): 3932–38. http://dx.doi.org/10.4049/jimmunol.156.10.3932.
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Abstract The mechanism of IL-12 production has been studied by stimulating macrophages or B cell lines with LPS, Staphylococcus aureus, or phorbol diester. However, since IL-12 plays an important role in the activation of T cells interacting with APC, it is important to study the mechanism of IL-12 production induced by T helper cell-APC interaction. We and others have demonstrated that IL-12 is produced in cultures where Th1 cells are stimulated with Ag or APC. In the present experiments, we studied a role of CD40-CD40 ligand (CD40L) interaction in IL-12 production and obtained the following results: 1) incubation of normal Th1 clone with APC in the presence of Ag induced IL-12 p40 and p35 mRNA accumulation and IL-12 production, and the addition of anti-CD40L blocked the p40 mRNA accumulation and IL-12 production but not p35 mRNA accumulation; 2) when Th1 clone from a CD40L-deficient mouse was used in the incubation, p35 mRNA accumulation was induced, but neither p40 mRNA accumulation nor IL-12 production was induced; 3) CD40L+ Th1 clone, or insect cell membrane expressing mouse CD40L, induced p40 mRNA accumulation and IL-12 production but not p35 mRNA accumulation. These results indicate that the CD40-CD40L interaction plays a critical role in IL-12 p40 mRNA accumulation and bioactive IL-12 production and that p35 mRNA accumulation was regulated via a different mechanism than CD40-CD40L interaction. Most of the cells producing IL-12 were Mac-1+ macrophages.
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Chen, Qing-Quan, Min Chen, Li-Hua Zhang, Yu Zeng, Liu Qi-Cai, Xiu-Lin Yang, and Xu-Chen Lin. "Costimulation blockade by combining CTLA4Ig with anti-CD40L mAb markedly inhibits the inflammatory response of experimental autoimmune myocarditis." European Journal of Inflammation 15, no. 1 (January 16, 2017): 28–34. http://dx.doi.org/10.1177/1721727x16686980.
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The aim of this study was to investigate the effect of costimulation blockade with cytotoxic T-lymphocyte-associated-antigen 4-immunoglobulin (CTLA4Ig) and anti-CD40L monoclonal antibody (anti-CD40L mAb) on an experimental autoimmune myocarditis (EAM) mouse model. Characteristics of myocardial tissue were observed by hematoxylin and eosin (H&E) staining. The messenger RNA (mRNA) levels of CTLA4, CD40L, IFN-γ, and IL-4 were detected by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR). Serum concentrations of IFN-γ and IL-4 were determined by ELISA. After immune intervention, the inflammatory score, mRNA levels of CTLA4 and CD40L, and IFN-γ level were decreased. Furthermore, these parameters in the combinational intervention group (blockade by CTLA4Ig and anti-CD40L mAb) were significantly decreased, compared to the single intervention group (blockade by CTLA4Ig or anti-CD40L mAb). However, after costimulation, blockade serum IL-4 levels were increased. Therefore, costimulation blockade by combination CTLA4Ig and anti-CD40L mAb could more effectively inhibit the inflammatory response of EAM than single use of CTLA4Ig or anti-CD40L mAb.
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Blossom, S., E. B. Chu, W. O. Weigle, and K. M. Gilbert. "CD40 ligand expressed on B cells in the BXSB mouse model of systemic lupus erythematosus." Journal of Immunology 159, no. 9 (November 1, 1997): 4580–86. http://dx.doi.org/10.4049/jimmunol.159.9.4580.
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Abstract Male BXSB mice, unlike female BXSB, develop a severe early onset lupus-like disease that has been linked to an intrinsic B cell defect. In investigating this B cell defect the present study showed that male, but not female, BXSB contained a higher percentage of large, activated splenic B cells that were more responsive to anti-CD40 mAb-induced proliferation. The hyperactivity of the large B cells from the male mice was also observed in the absence of anti-CD40 mAb or any other stimuli. In examining the mechanism of the B cell hyperactivity, it was found that 20% of unstimulated large B cells from male mice, unlike large B cells from female mice, expressed CD40 ligand (CD40L), a molecule normally expressed on activated CD4+ cells. The percentage of large B cells from the male BXSB that expressed CD40L was increased to 43% by stimulation with LPS. A functional role for CD40L expression on B cells was confirmed by showing that CD40-Ig blocked the spontaneous proliferation of the large B cells from male mice. In addition, the stimulatory capacity of the large B cells from the male mice was demonstrated by their ability to induce DNA synthesis in small B cells in a CD40L-dependent manner. These results demonstrated that large B cells from male BXSB expressed functionally active CD40L. It is likely that the B cell CD40L expression and increased susceptibility to CD40 signaling due to an intrinsic B cell hyperactivity promotes autoimmune disease in BXSB mice.
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Sarma, Jayasri Das, Fareeha Saadi, Debanjana Chakravarty, Saurav Kumar, Mithila Kamble, Reas Khan, and Kenneth S. Shindler. "CD40-CD40L interaction is critical in mounting host immunity against m-CoV Mouse Hepatitis Virus induced neuroinflammatory demyelination." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 53.05. http://dx.doi.org/10.4049/jimmunol.206.supp.53.05.
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Abstract Chronic progressive neuroinflammatory disease multiple sclerosis (MS) is characterized by loss of neuronal functions resulting from demyelination with or without axonal degeneration. Infiltration of T lymphocytes and activation of microglia and their interplay are the major pathophysiological events leading to neurodegeneration in MS. Our studies in Mouse Hepatitis Virus (MHV) induced neuroinflammatory model demonstrated a protective role of CNS infiltrating CD4+ T cells. In the absence of CD4+ T cells, microglial activation fails to resolve, and mice are more susceptible to acute poliomyelitis and chronic demyelination with axonal bulbar vacuolation. Our studies also revealed that CD40L (expressed on CD4+ T cells) upregulates upon MHV infection but is downregulated in CD4−/− mice CNS. This led to a further delineation of the CD4-microglia nexus at the molecular level using CD40L−/− mice. Results showed that the absence of CD40L renders mice highly susceptible to MHV infection due to reduced microglia/macrophage activation and significantly dampened effector CD4+ T recruitment to the CNS at the acute-adaptive bridging phase (day 7–10 p.i.) of inflammation. Moreover, CD40L−/− mice exhibited severe demyelination, axonal loss, and persistent poliomyelitis at the chronic phase of infection, highlighting the protective role of CD40-CD40L in MHV induced neuroinflammatory demyelination. Together, these studies highlight that migration of peripheral T cells and their interaction with microglia via CD40-CD40L is essential to eliminate the virus and provide long-term neuroprotection. These findings can lead to designing potential therapeutic interventions against MS, targeting CD40-CD40L interaction.
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Ralph, Kerry L. M., Mark Panzenbeck, Haiguang Xiao, Lee Frego, Tammy Bigwarfe, Erica Waltz, Christine Grimaldi, et al. "Identification and characterization of an antagonistic anti-mouse CD40 antibody." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 70.19. http://dx.doi.org/10.4049/jimmunol.196.supp.70.19.
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Abstract Targeting CD40-CD40L interactions has been an interesting drug concept for the treatment of autoimmune diseases given this pathway’s role in the development of both humoral and cell mediated immune responses. While preclinical blockade of CD40L is well documented in various autoimmune animal models of disease, limited data exists for CD40 blockade due to lack of a truly antagonistic anti-mouse CD40 tool antibody (Ab). Here we describe the in vitro and in vivo characterization of a fully antagonistic anti-mouse CD40 monoclonal Ab (BI CD40-1); a chimeric rat Fv anti-mouse CD40 mAb engineered with a mouse IgG2a Fc containing mutations to abrogate Fcγ receptor binding. BI CD40-1 blocks molecular CD40-CD40L interactions (IC50 = 0.25 nM) and exhibits potent binding to CD40 expressed on mouse B cells (EC50 = 0.42 nM ± 0.08). In vitro profiling of BI CD40-1 using a mouse splenocyte proliferation assay confirmed potent antagonistic activity (IC50 = 0.27 nM ± 0.09) as well as absence of any agonistic properties (stimulation index < 2 @ 67 nM). Administration of BI CD40-1 to mice prior to ovalbumin (OVA) immunization resulted in dose-dependent blockade of OVA-specific IgG responses (100, 100, 74, 0% inhibition at 10, 3, 1, and 0.3 MPK; day 13) correlating with similar dose dependent receptor occupancy and inhibition of B cell activation as measured by ex vivo CD54 upregulation. Prophylactic dosing in cGVHD model of scleroderma showed dose dependent protection in disease development as seen by decreased dermal thickness, myofibroblast counts and collagen deposition. BI CD40-1 represents a novel fully antagonistic anti-mouse CD40 mAb, an important tool for mechanistic understanding of the therapeutic value of targeting of CD40 in inflammatory diseases.
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Lopez-Saucedo, Catalina, Rodolfo Bernal-Reynaga, Jesus Zayas-Jahuey, Silvia Galindo-Gomez, Mineko Shibayama, Carlos Garcia-Galvez, Sergio Estrada-Parra, and Teresa Estrada-Garcia. "CD40 Ligand Deficient C57BL/6 Mouse Is a Potential Surrogate Model of Human X-Linked Hyper IgM (X-HIGM) Syndrome for Characterizing Immune Responses against Pathogens." BioMed Research International 2015 (2015): 1–11. http://dx.doi.org/10.1155/2015/679850.
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Individuals with X-HIGM syndrome fail to express functional CD40 ligand; consequently they cannot mount effective protective antibody responses against pathogenic bacteria. We evaluated, compared, and characterized the humoral immune response of wild type (WT) and C57-CD40L deficient (C57-CD40L−/−) mice infected withCitrobacter rodentium. Basal serum isotype levels were similar for IgM and IgG3 among mice, while total IgG and IgG2b concentrations were significantly lower in C57-CD40L−/−mice compared with WT. Essentially IgG1 and IgG2c levels were detectable only in WT mice. C57-CD40L−/−animals, orally inoculated with2×109CFU, presented several clinical manifestations since the second week of infection and eventually died. In contrast at this time point no clinical manifestations were observed among C57-CD40L−/−mice infected with1×107CFU. Infection was subclinical in WT mice inoculated with either bacterial dose. The serum samples from infected mice (1×107CFU), collected at day 14 after infection, had similarC. rodentium-specific IgM titres. Although C57-CD40L−/−animals had lower IgG and IgG2b titres than WT mice, C57-CD40L−/−mice sera displayed complement-mediated bactericidal activity againstC. rodentium.C. rodentium-infected C57-CD40L−/−mice are capable of producing antibodies that are protective. C57-CD40L−/−mouse is a useful surrogate model of X-HIGM syndrome for studying immune responses elicited against pathogens.
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Gurunathan, Sanjay, Kari R. Irvine, Chang-You Wu, Jeffrey I. Cohen, Elaine Thomas, Calman Prussin, Nicholas P. Restifo, and Robert A. Seder. "CD40 Ligand/Trimer DNA Enhances Both Humoral and Cellular Immune Responses and Induces Protective Immunity to Infectious and Tumor Challenge." Journal of Immunology 161, no. 9 (November 1, 1998): 4563–71. http://dx.doi.org/10.4049/jimmunol.161.9.4563.
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Abstract CD40/CD40 ligand interactions have a central role in the induction of both humoral and cellular immunity. In this study, we examined whether a plasmid expressing CD40 ligand/trimer (CD40LT) could enhance immune responses in vivo. BALB/c mice were injected with plasmid expressing β-galactosidase DNA with or without CD40LT DNA or IL-12 DNA, and immune responses were assessed. Mice vaccinated with β-gal DNA plus CD40LT DNA or IL-12 DNA had a striking increase in Ag-specific production of IFN-γ, cytolytic T cell activity, and IgG2a Ab. The mechanism by which CD40LT DNA enhanced these responses was further assessed by treating vaccinated mice with anti-IL-12 mAb or CTLA-4 Ig (CTLA4Ig). Production of IFN-γ and CTL activity was abrogated by these treatments, suggesting that CD40LT DNA was mediating its effects on IFN-γ and CTL activity through induction of IL-12 and enhancement of B7 expression, respectively. Physiologic relevance for the ability of CD40LT DNA to enhance immune responses by the aforementioned pathways was shown in two in vivo models. First, with regard to CTL activity, mice vaccinated with CD40LT DNA did not develop metastatic tumor following challenge with lethal dose of tumor. Moreover, in a mouse model requiring IL-12-dependent production of IFN-γ, mice vaccinated with soluble Leishmania Ag and CD40LT DNA were able to control infection with Leishmania major. These data suggest that CD40LT DNA could be a useful vaccine adjuvant for diseases requiring cellular and/or humoral immunity.
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Balasa, B., T. Krahl, G. Patstone, J. Lee, R. Tisch, H. O. McDevitt, and N. Sarvetnick. "CD40 ligand-CD40 interactions are necessary for the initiation of insulitis and diabetes in nonobese diabetic mice." Journal of Immunology 159, no. 9 (November 1, 1997): 4620–27. http://dx.doi.org/10.4049/jimmunol.159.9.4620.
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Abstract The nonobese diabetic (NOD) mouse spontaneously develops T cell-dependent autoimmune diabetes. Here, we investigate the role of CD40 ligand (CD40L)-CD40 costimulation in the initiation and progression of this disease. Anti-CD40L mAb treatment of 3- to 4-wk-old NOD females (the age at which insulitis typically begins) completely prevented the insulitis and diabetes. In contrast, treatment of such mice with anti-CD40L at >9 wk of age did not inhibit the disease process. These results suggest that a costimulatory signal by CD40L is required early but not in the effector phase of disease development. Anti-CD40L treatment affected the priming of islet Ag-specific T cell responses in vivo. Cytokine analysis revealed a dramatic decrease in IFN-gamma and IL-2 release without a concomitant increase in IL-4 production by T cells from anti-CD40L-treated mice. Thus, anti-CD40L impaired the islet Ag-specific Th1 cell response in vivo, and the prevention of diabetes by anti-CD40L was not associated with switching of the response from a Th1 to a Th2 profile. Cotransfer of splenocytes from anti-CD40L-treated mice with splenocytes from diabetic NOD mice into NOD/scid mice did not inhibit the transfer of disease, indicating that anti-CD40L does not prevent the disease by inducing regulatory cells. Since anti-CD40L clearly prevented the insulitis by inhibiting the development and further accumulation of pathogenic Th1 cells to islets of Langerhans, we conclude that CD40L-CD40 costimulation is required for early events in the development of spontaneous autoimmune diabetes.
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Wiley, J. A., and A. G. Harmsen. "CD40 ligand is required for resolution of Pneumocystis carinii pneumonia in mice." Journal of Immunology 155, no. 7 (October 1, 1995): 3525–29. http://dx.doi.org/10.4049/jimmunol.155.7.3525.
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Abstract The role of the CD40-CD40 ligand (CD40L) interaction in resolution of Pneumocystis carinii (PC) pneumonia (PCP) was assessed in a PC-infected severe combined immunodeficiency (SCID) mouse reconstitution model using an anti-CD40L mAb to block CD40L. SCID mice infected with PC were reconstituted with unfractionated spleen cells from immunocompetent donors and given either anti-CD40L mAb or an irrelevant control mAb. Mice given the control mAb resolved the PC infection, whereas those given the anti-CD40L mAb did not. That anti-CD40L mAb also inhibited PC-specific IgG production is consistent with the possibility that cognate CD4+ T cell-B cell interactions are important in PCP resolution. The experiment was then repeated, except that the PC-infected SCID mice were reconstituted with purified CD4+ T cells only. Again, the control mAb-treated group resolved the PCP, whereas mice treated with anti-CD40L mAb did not. In the second experiment, inhibition of resolution of PCP in the anti-CD40L mAb group was not the result of blocking CD4+ T cell-dependent activation of PC-specific B cells. The results are consistent with the possibility that resistance to PCP may involve interaction between B cells and CD4+ T cells via the CD40-CD40L pathway. However, results additionally indicate that inhibition of CD40-CD40L interaction ablates resistance to PCP by inhibiting the interaction of T cells with some cell other than B cells.
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Snyder, James T., Jijia Shen, Hooman Azmi, Jeannie Hou, Daniel H. Fowler, and Jack A. Ragheb. "Direct inhibition of CD40L expression can contribute to the clinical efficacy of daclizumab independently of its effects on cell division and Th1/Th2 cytokine production." Blood 109, no. 12 (June 15, 2007): 5399–406. http://dx.doi.org/10.1182/blood-2006-12-062943.
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Abstract Humanized anti-CD25 antibodies (eg, daclizumab) have been successfully used to treat several autoimmune diseases. Paradoxically, IL-2 blockade in mice can induce autoimmunity. An interspecies difference in the relative contribution of IL-2 to CD25+ T regulatory cell (CD25+Treg) versus CD25+ effector cell function might explain this conundrum. Consistent with this are reports that daclizumab inhibits human CD25+ effector cell cytokine production by blocking the expression of CD40L. However, in mice, IL-4 and IL-12 regulate CD40L expression. As human Th1/Th2 cytokine production is also dependent on IL-2, daclizumab's inhibition of CD40L expression could be due to an indirect, rather than a direct, effect of IL-2. Here, we clarify the mechanisms underlying CD40L expression. In contrast to the mouse, human CD40L is regulated by CD28 signaling and IL-2, not the principal Th1/Th2-polarizing cytokines. We find that CD40L is expressed on naive and memory cells and inhibited by daclizumab independently of cell division. Collectively, our results indicate that daclizumab could inhibit CD25+ effector T-cell function in vivo by directly blocking CD40L expression. This difference between mice and human may help explain the paradoxical effects of IL-2R blockade in the 2 species.
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Wang, Qiuli, Muwen Yang, Ye Zhang, Li Zhong, and Xinyu Zheng. "Novel Combination Oncolytic Adenoviral Gene Therapy Armed with Dm-dNK and CD40L for Breast Cancer." Current Gene Therapy 19, no. 1 (May 28, 2019): 54–65. http://dx.doi.org/10.2174/1566523219666190307094713.
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Background:Both Drosophila melanogaster deoxyribonucleoside kinase (Dm-dNK) suicide gene therapy and exogenous CD40 ligand (CD40L)-CD40 interaction in cancer via conditionally replicating adenovirus can selectively kill tumors without damaging normal tissues.Objective:To further improve the cancer killing effect, we investigated the therapeutic effect of combined cancer gene therapy based on a selective oncolytic adenovirus vector containing Dm-dNK suicide gene and exogenous CD40L on breast carcinoma cells in vitro and in vivo.Methods:A series of conditionally replicating adenoviruses using adenovirus vector P74 were generated: P74-dNK, P74-CD40L (expressing Dm-dNK or CD40L respectively), and P74-dNK-CD40L (expressing combined Dm-dNK and CD40L). Breast cancer cell lines (MDA-MB-231, MCF-7) and non-tumor cell line (MRC5) were treated with adenovirus and cytotoxicity determined by MTT assay, and apoptosis assessed by flow cytometry after 72h. We also assessed in vivo cell killing efficiency using a mouse xenograft model with MDA-MB-231 cells.Results and Discussion:Co-expression of Dm-dNK and CD40L reduced cell proliferation of MDAMB- 231 or MCF7 cancer cells, and induced more apoptosis in TERT and CD40 positive cancer cells, but not normal MRC5 cells. Significant reduction in tumor volume was also seen in combined treatment arms as compared to any single treatment.Conclusion:Our data suggest enhanced, selective tumor cell killing using combined gene therapy with conditionally replicating adenovirus containing Dm-dNK suicide gene and exogenous CD40 ligation (CD40L-CD40).
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Tay, Neil, Nayana Prabhu Padubidhri, Hok Sum Wong, Yen Chua, and David Kemeny. "Expression of CD40L on CD8 T cells and its role in influenza A infection (IRC5P.618)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 58.1. http://dx.doi.org/10.4049/jimmunol.194.supp.58.1.
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Abstract CD8 T cells play an important role in protective immunity against a wide range of pathogens and the factors that control their activation are clearly important. CD40L-mediated CD40 licensing of dendritic cells by CD4 T cells is known to be necessary for the generation of a robust CD8 T cell response. Less clear is the contribution of CD40L on CD8 T cells to their activation. We have previously shown that CD8 T cells are able to induce the production of IL-12 p70 by dendritic cells in a CD40L-dependent manner. To better understand the role of CD40L on CD8 T cells responses, we generated and characterized CD40L-expressing CD8 T cells both in vitro and in vivo. We found that CD40L is expressed on 30-50% of activated effector CD8 T cells and the differentiation of CD8 T cells into CD40L-expressing cells is strongly induced by IL-12, suggesting the presence of a positive feedback mechanism mediated by CD40L and IL-12. Using an influenza A mouse model, we examined whether this mechanism is involved in the primary expansion of CD8 T cells during an infection and whether CD40L-expressing CD8 T cells are able to license dendritic cells for optimal memory CD8 T cell programming. In the absence of CD40L signaling, the ability to upregulate CD25 and downregulate CD62L is diminished in CD8 T cells, causing an impairment in their primary expansion and also their ability to accumulate at the site of infection.
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Amirkhosravi, Ali, Todd V. Meyer, Liza Robles-Carillo, Monica Davila, Florian Langer, Hina Desai, Patricia Weinstein, Mildred Amaya, Eduardo Reyes, and John L. Francis. "Mechanism of Thrombocytopenia Induced by Anti-CD40 Ligand Immune Complexes and the Prevalence of CD40 Ligand Autoantibodies in Patients with Thrombotic Autoimmune Disorders." Blood 112, no. 11 (November 16, 2008): 2857. http://dx.doi.org/10.1182/blood.v112.11.2857.2857.
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Abstract Anti-CD40 ligand (anti-CD40L) immunotherapy in patients with systemic lupus erythematosus (SLE, a chronic inflammatory autoimmune disease) resulted in unexpected thromboembolic fatalities. In our laboratory, previous in vitro mechanistic (flow cytometry, aggregation, and dense granule release) studies have shown that monoclonal anti-CD40L immune complexes potently activate platelets via the IgG receptor (FcγRIIa). The data suggested this activity was also dependent on the CD40L receptor (CD40), which is constitutively expressed on resting and activated platelets. This raised the possibility that autoantibodies against CD40L maybe present in patients with thrombotic autoimmune diseases such as SLE and anti-phospholipid syndrome (APS) and possibly contribute to the pathogenesis of thrombosis in such patients. We hypothesized that monoclonal anti-CD40L immune complexes (anti-CD40L IC) should exhibit prothrombotic effects in animals via IC-induced platelet activation, and CD40 ligand autoantibodies may be prevalent in patients with thrombotic auto-immune disorders. Mouse platelets, however, do not carry FcγRIIa. Therefore, to study anti-CD40L IC-induced platelet activation in vivo, we used mice transgenic for human FcγRIIa (“hFcR” mice). Immune complexes consisting of the anti-CD40L monoclonal antibody, M90, plus recombinant soluble CD40L (M90+sCD40L), or control reagents were injected intravenously (tail vein) into wild type (WT) or hFcR mice. Platelets were counted from 10–60 minutes thereafter. Additionally, plasma samples from patients with SLE (n=54), APS, (n=8), idiopathic thrombosis (n=34), and control subjects (n=86) were tested for the presence of IgG-type anti-CD40L autoantibodies using a highly optimized in-house ELISA. The injection of M90+CD40L IC (100–500 nM) produced symptoms consistent with thrombotic shock and induced severe thrombocytopenia (10–30% of basal platelet count) in hFcR (n=10–20) but not WT (n=5) mice—indicating that IC-induced thrombocytopenia was mediated via platelet FcγRIIa, as was found in vitro. Platelet priming by subaggregatory amounts of ADP greatly increased the sensitivity of hFcR mice to anti-CD40L IC (≥ eight-fold—as low as 12.5 nM). Furthermore, sequential injections of sCD40L followed by M90 in hFcR mice caused similar effects, indicating that ICs can also form while circulating. Injections of M90 or sCD40L alone were inactive in all animals. The prevalence of CD40L autoantibodies was notably higher in patients with SLE or APS compared to control subjects [13/54 (24%) or 3/12 (25%) vs. 5/86 (6%), P=0.002 and P=0.09 respectively]. Although CD40L autoantibodies were also more prevalent in patients with SLE and APS than in those with idiopathic thrombosis [2/34 (6%)], this difference was not statistically significant (P=0.058 and 0.2 respectively). Our findings demonstrate that the platelet activation caused by of anti-CD40L IC can be reproduced in mice, but only in those transgenic for the human IgG receptor (Fcγ RIIa). These in vivo findings may shed light on the thromboembolic complications associated with CD40L immunotherapy. Furthermore, our hFcR mouse model is a promising approach for assessing the hemostatic safety of CD40L—and possibly other—therapeutic antibodies. Our results also show that autoantibodies to CD40L occur at relatively high frequency in patients with SLE and APS. While a causal relationship between such antibodies and thrombotic risk remains unidentified, our in vivo studies suggest further investigation is warranted.
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Chen, Lili, Wen Cheng, Pooja Shivshankar, Lei Lei, Xiaoyun Zhang, Yimou Wu, I.-Tien Yeh, and Guangming Zhong. "Distinct Roles of CD28- and CD40 Ligand-Mediated Costimulation in the Development of Protective Immunity and Pathology during Chlamydia muridarum Urogenital Infection in Mice." Infection and Immunity 77, no. 7 (April 27, 2009): 3080–89. http://dx.doi.org/10.1128/iai.00611-08.
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ABSTRACT Infection with Chlamydia muridarum in the mouse urogenital tract can induce both protective immunity and inflammatory pathologies, which has been used as a model for understanding the immune and pathogenic mechanisms of C. trachomatis infection. We compared the roles of CD28- and CD40 ligand (CD40L)-mediated costimulation in C. muridarum infection. Mice with CD28 or CD80/CD86 gene knockout (KO) displayed an infection course similar to that of wild-type mice during both primary and secondary infection, suggesting that CD28-mediated costimulation is not required for protection against C. muridarum infection. However, mice deficient in CD40L or CD40 displayed a prolonged infection course after primary or secondary infection, suggesting that CD40-CD40L costimulation plays an essential role in the development of anti-C. muridarum immunity. Interestingly, the CD28- or CD80/CD86-deficient mice displayed significantly lower levels of inflammatory pathologies in the upper genital tracts after primary infection, although the attenuation in inflammation was no longer significant during secondary infection. However, the CD40L or CD40 KO mice developed inflammatory pathologies as severe as those in wild-type mice following either primary or secondary infection despite the obvious deficits in adaptive immunity in these KO mice. The resistance of CD28 or CD80/CD86 KO mice to chlamydial infection correlated with production of gamma interferon, while the development of inflammatory pathologies in CD40L or CD40 KO mice correlated with the production of other proinflammatory cytokines in mouse urogenital tracts during the early stages of the infection. These observations together suggest that C. muridarum-induced protective immunity and inflammatory pathologies can be mediated by distinct costimulatory signals.
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Chamekh, Mustapha, Vincent Vercruysse, Mohammed Habib, Maxime Lorent, Michel Goldman, Abdelmounaïm Allaoui, and Bernard Vray. "Transfection of Trypanosoma cruzi with Host CD40 Ligand Results in Improved Control of Parasite Infection." Infection and Immunity 73, no. 10 (October 2005): 6552–61. http://dx.doi.org/10.1128/iai.73.10.6552-6561.2005.
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ABSTRACT We have previously shown that infection by Trypanosoma cruzi, a parasitic protozoan, is reduced by injection of CD40 ligand (CD40L)-transfected 3T3 fibroblasts (D. Chaussabel, F. Jacobs, J. de Jonge, M. de Veerman, Y. Carlier, K. Thielemans, M. Goldman, and B. Vray, Infect. Immun. 67:1929-1934, 1999). This prompted us to transfect T. cruzi with the murine CD40L gene and to study the consequences of this transfection on the course of infection. For this, epimastigotes (Y strain) were electroporated with the pTEX vector alone or the pTEX-CD40L construct, and transfected cells were selected for their resistance to Geneticin G418. Then strain Y-, pTEX-, and pTEX-CD40L-transfected epimastigotes were transformed by metacyclogenesis into mammalian infective forms called Y, YpTEX, and YpTEX-CD40L trypomastigotes. Transfection of the CD40L gene and expression of the CD40L protein were assessed by reverse transcription-PCR and Western blot analysis. The three strains of parasites were infective in vitro for mouse peritoneal macrophages. When organisms were inoculated into mice, a very low level of parasitemia and no mortality were seen with the YpTEX-CD40L strain compared to the Y and YpTEX strains. Furthermore, the proliferative capacity and the secretion of gamma interferon were both preserved in spleen cells (SCs) from YpTEX-CD40L-infected mice but not with SCs from Y- and YpTEX-infected mice. These results suggest that the CD40L produced by transfected T. cruzi is involved in the modulation of an antiparasite immune response. Moreover, mice surviving YpTEX-CD40L infection resisted a challenge infection with the wild-type strain. Taken together, our data demonstrate the feasibility of generating a T. cruzi strain expressing a bioactive host costimulatory molecule that counteracts the immunodeficiency induced by the parasite during infection and enhances protective immunity against a challenge infection.
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He, Qing, Linlin Liu, Qiaoyu Yang, Ailing Wang, Shuo Chen, Ruiyun Li, Yi Huang, et al. "Invariant natural killer T cells promote immunogenic maturation of lung dendritic cells in mouse models of asthma." American Journal of Physiology-Lung Cellular and Molecular Physiology 313, no. 6 (December 1, 2017): L973—L990. http://dx.doi.org/10.1152/ajplung.00340.2016.
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Our previous study showed that invariant natural killer T (iNKT) cells might act as an adjuvant to promote Th2 inflammatory responses in an OVA-induced mouse model of allergic asthma, but the mechanism remains unknown. To clarify the underlying mechanism through which iNKT cells promote Th2 inflammatory responses, we investigated the modulatory influence of iNKT cells on phenotypic and functional maturation of lung dendritic cells (LDCs) using iNKT cell-knockout mice, specific iNKT cell activation, coculture experiments, and adoptive transfer of iNKT cells in mouse models of asthma. Our data showed that iNKT cell deficiency could downregulate surface maturation markers and proinflammatory cytokine secretion of LDCs from a mouse model of asthma. However, elevated activation of iNKT cells by α-galactosylceramide and adoptive transfer of iNKT cells could upregulate surface maturation markers and proinflammatory cytokine secretion of LDCs from mouse models of asthma. Meanwhile, iNKT cells significantly influenced the function of LDCs, markedly enhancing Th2 responses in vivo and in vitro. In addition, iNKT cell can induce LDCs expression of CD206 and RELM-α, reflecting alternative activation of LDCs in a mouse model of asthma. α-Galactosylceramide treatment significantly enhanced expression of CD40L of lung iNKT cells from a mouse model of asthma, and the coculture experiment of LDCs with iNKT cells showed that the blockade of CD40L strongly suppressed surface maturation markers and proinflammatory cytokine production by LDCs. Our data suggest that iNKT cells can promote immunogenic maturation of LDCs to enhance Th2 responses in mouse models of asthma.
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Rossi, Gabriela, Jolly Sarkar, and Dorothea Scandella. "Long-term induction of immune tolerance after blockade of CD40-CD40L interaction in a mouse model of hemophilia A." Blood 97, no. 9 (May 1, 2001): 2750–57. http://dx.doi.org/10.1182/blood.v97.9.2750.
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Abstract A factor VIII–deficient knockout mouse was used as a model for severe hemophilia A to characterize the immune response to recombinant human factor VIII (fVIII) and to study new approaches for induction of immune tolerance to fVIII. Mice initially received periodic injections of fVIII in doses similar to those used for the treatment of human hemophilia A. To induce immune tolerance, a hamster monoclonal antibody specific for murine CD40 ligand (CD40L or CD154) was injected with fVIII. Control mice received fVIII alone or fVIII and hamster immunoglobulin G. After treatment, humoral and cellular immune responses were evaluated. Ninety-five percent of anti-CD40L–treated mice had lower titers of anti-fVIII antibody (less than 1 μg/mL) compared with fVIII-injected control mice (mean, 18 μg/mL). To determine whether anti-CD40L treatment induces long-term immune tolerance, mice were rechallenged 3 times with fVIII alone. At 150 days after treatment, 12 of 22 anti-CD40L–treated mice remained tolerant to fVIII (anti-fVIII antibody titers less than 1 μg/mL). However, tolerant mice immunized with tetanus toxoid (TT) developed high anti-TT antibody, demonstrating that tolerance is fVIII specific. T cells from tolerant mice showed impaired proliferative responses after stimulation with fVIII in vitro and lack of production of the cytokines interleukin-2 (IL-2), IL-4, interferon γ, and IL-10. These results demonstrate that long-term immune tolerance to fVIII was effectively induced after early blockade of CD40-CD40L interaction. In addition, the lack of tolerance in this model was associated with the expression of a Th2 phenotype.
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Bai, Yun, Demian Obregon, Huayan Hou, William Nikolic, Takashi Mori, Jin Zeng, Jared Ehrhart, et al. "Active Aβ vaccination-induced Aβ clearance enhanced by suppression of the CD40-CD40L interaction (48.11)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S76. http://dx.doi.org/10.4049/jimmunol.178.supp.48.11.
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Abstract Active and passive Aβ immunization efficiently reduces amyloid plaque load and memory impairment in transgenic mouse models of Alzheimer’s disease. Immunization has also yielded favorable results for many patients; but a significant percentage also developed severe meningioencephalitis. Prior studies by our group suggest CD40 receptor-CD40 ligand interaction between T-cells and microglia initiates release of proinflammatory factors, which drive phenotypic switching from a phagocytic to an antigen presenting cell phenotype thus impairing the clearance of Aβ. We therefore tested whether a CD40 blockade could enhance Aβ vaccination-mediated Aβ clearance in vivo. Importantly in our present study, Aβ vaccinated CD40 deficient heterozygous transgenic mice over-expressing mutant amyloid precursor protein and presenilin-1 demonstrated enhanced Aβ clearance; compared with vaccinated PSAPP mice. Similar results were obtained with Aβ vaccinated PSAPP mice passively immunized with CD40L antibody injections. Taken together with our previous studies these data suggest that CD40 blockade, in the context of active Aβ vaccination, acts to enhance CNS Aβ clearance by maintaining microglia in a phagocytic phenotype. These data also may provide the basis for a method whereby enhancing Aβ vaccination-mediated Aβ clearance strategies.
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Warren, W. D., and M. T. Berton. "Induction of germ-line gamma 1 and epsilon Ig gene expression in murine B cells. IL-4 and the CD40 ligand-CD40 interaction provide distinct but synergistic signals." Journal of Immunology 155, no. 12 (December 15, 1995): 5637–46. http://dx.doi.org/10.4049/jimmunol.155.12.5637.
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Abstract The interaction between B cell CD40 and its ligand (CD40L) on activated Th cells provides a critical signal necessary for T cell-dependent isotype switching. Previous studies suggest that this signal might be important in regulating isotype switching at the level of germ-line Ig transcription. To assess the effects of the CD40L-CD40 interaction on germ-line Ig transcript expression in murine B cells, a membrane-bound form of mouse CD40L was expressed in the baculovirus system. We show that stimulation of resting splenic B cells with CD40L-expressing Sf9 cells induces germ-line gamma 1 and epsilon transcripts independently of cytokines. The CD40-mediated induction cannot be blocked by anti-IL-4 Ab and is not mediated by other cytokines secreted endogenously in response to CD40 stimulation. Importantly, stimulation with CD40L and IL-4 together has a significant synergistic effect on germ-line transcript expression. Stimulation of CD40 does not activate the NF-IL-4-gamma 1 DNA binding factor believed to be required for IL-4-dependent germ-line gamma 1 transcription. Moreover, mutation of the NF-IL-4-gamma 1 DNA binding site in a germ-line gamma 1 promoter-luciferase reporter gene construct completely ablates IL-4 responsiveness but has no effect on responsiveness to CD40L in transient transfection assays. These results demonstrate that the CD40L-CD40 interaction and IL-4 activate germ-line Ig gene transcription by distinct but synergistic mechanisms and suggest that multiple signals may be required to induce sufficient germ-line transcription and/or germ-line transcript levels necessary to target switch recombination.
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Lucas, Carrie L., Thomas Fehr, Fabienne Haspot, and Megan Sykes. "CD40L-specific mAb mediates its tolerogenic effects through engagement of FcgRIIB, not via depletion of activated T cells (141.17)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 141.17. http://dx.doi.org/10.4049/jimmunol.182.supp.141.17.
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Abstract Objective: To determine the mechanism by which a widely used anti-mouse CD40L mAb (clone MR1) given with allogeneic bone marrow cells (BMCs) tolerizes peripheral CD8 T cells. Methods: B6 mice received 3Gy total body irradiation one day prior to ip injection of 2mg a-CD40L & iv infusion of 25x106 MHC-mismatched B10.A BMCs. This regimen induces long-term mixed chimerism, as measured by durable presence of donor leukocytes, without depletion of recipient CD4 or CD8 T cells. Results: Although genetic deficiency of CD40L alone allowed graft acceptance in recipients depleted of CD8 cells, it did not prevent rejection in mice replete with CD8 T cells. Thus, Fc-dependent functions of a-CD40L were studied. A role for complement was excluded, as 4/5 C3 KO recipients became chimeric. CD8 T cell-intrinsic CD40L was dispensable (3/5 chimeras each in mice with WT or KO CD8 cells), indicating that a-CD40L need not act directly on CD8 cells. However, FcgRIIB KO recipients promptly rejected donor BM unless CD8 T cells were depleted (5/7, 0/5, 7/8, & 5/7 chimeras for WT, KO, WT + a-CD8, & KO + a-CD8 groups, respectively). Recipient B cells are the likely source of FcgRIIB, as DC-derived FcgRIIB was not essential (4/6 chimeras each in mice with WT or KO DC). Conclusions: A-CD40L with allogeneic BMCs generates immune complexes that ligate FcgRIIB, inducing as yet undefined downstream effects essential for CD8 T cell tolerance. Supported by NIH Grant RO1 49915 & NDSEG Fellowship.
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Vowinkel, Thorsten, Katherine C. Wood, Karen Y. Stokes, Janice Russell, Christian F. Krieglstein, and D. Neil Granger. "Differential expression and regulation of murine CD40 in regional vascular beds." American Journal of Physiology-Heart and Circulatory Physiology 290, no. 2 (February 2006): H631—H639. http://dx.doi.org/10.1152/ajpheart.00733.2005.
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There is emerging evidence for a role of the CD40/CD40 ligand (CD40L) dyad as a signaling mechanism in different inflammatory conditions. The aims of this study were to 1) quantify the constitutive and induced expression of CD40 in different regional vascular beds of the mouse and 2) assess the role of CD40L as a modulator of vascular endothelial CD40 expression. The dual radiolabeled monoclonal antibody technique was used to quantify the expression of endothelial CD40 in control and LPS-challenged wild-type (WT) mice. Significant constitutive CD40 expression was detected in several vascular beds of WT mice with lung, kidney, and small intestine exhibiting the highest expression, whereas the liver and stomach showed no detectable baseline expression. LPS administration elicited two- to sevenfold increases in CD40 expression in several tissues (heart, kidney, and intestine) within 4 h, whereas other organs (brain) required up to 48 h to exhibit CD40 upregulation. CD40 expression was not detected in unstimulated or LPS-challenged CD40−/− mice. Constitutive expression of CD40 was profoundly reduced in unstimulated CD40L−/− mice, but the LPS-induced CD40 upregulation did not differ between CD40L−/− and WT mice. Depletion of platelets or T lymphocytes, the major CD40L-expressing cells in blood, also resulted in a profound reduction in basal CD40 expression. These findings demonstrate significant endothelial expression of CD40 under basal conditions in different vascular beds and increased CD40 expression after endothelial cell activation with LPS. Platelet- and T-lymphocyte-associated CD40L appears to play a major role in regulating the density of CD40 expression on vascular endothelial cells in vivo.
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Yanagawa, Senichiro, Hiroyuki Tahara, Takayuki Shirouzu, Shintaro Kawai, Yuka Tanaka, Kentaro Ide, Shuji Akimoto, and Hideki Ohdan. "Development of a humanized mouse model to analyze antibodies specific for human leukocyte antigen (HLA)." PLOS ONE 16, no. 2 (February 5, 2021): e0236614. http://dx.doi.org/10.1371/journal.pone.0236614.
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In organ transplantation, human leukocyte antigen (HLA)-mismatch grafts not only induce the activation of cellular mediated immune response but also the development of chronic antibody-mediated rejection due to the donor-specific anti-HLA antibody (DSA) produced by B cells and plasma cells interacting with the graft endothelium. Significant improvement in long-term survival after transplantation can be expected if antibody-mediated rejection due to the DSA can be overcome. However, the mechanism of producing or controlling the DSA remains to be elucidated. In recent decades, “humanized” mouse models have been widely used for the basic research of human immune systems, but a humanized mouse model to analyze the mechanism of DSA production has not been established yet. Thus, we aimed to create a humanized mouse using a severe immunodeficiency mouse (NSG mouse) administered with human peripheral blood mononuclear cells (PBMCs). Initially, we detected a very low level of human total-IgG and no anti-HLA antibodies (Abs) in these mice. In our next attempt, we mixed PBMCs of various HLA antigenic combinations with or without regulatory T cells and preconditioned them by culturing on feeder cells stably transfected with human CD40 ligand (h-CD40L) alone or with h-CD40L and human B cell activating factor (h-BAFF). They were subsequently co-cultured with the corresponding irradiated stimulator PBMCs, and all cells were administered into naïve NSG mice. Although all three humanized models had sufficient human total-IgG and anti-HLA antibody production, allospecific anti-HLA Ab production was prominently suppressed whereas non-specific anti-HLA Abs were sufficiently detected. Therefore, this novel humanized mouse model might be useful for analyzing the mechanism of anti-allogeneic human B cell tolerance induction.
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Hashem, Anwar M., Abdullah Algaissi, Anurodh Agrawal, Sawsan Al-amri, Abdulrahman Almasoud, Naif Alharbi, Bi-Hung Peng, Xuguang Li, and Chien-Te Tseng. "CD40-targeted S1 subunit vaccine protects against MERS-CoV and S1-associated pulmonary immunopathology in transgenic human DPP4 mouse model." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 139.10. http://dx.doi.org/10.4049/jimmunol.202.supp.139.10.
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Abstract Middle East respiratory syndrome coronavirus (MERS-CoV) is a highly pathogenic respiratory virus that emerged in 2012. While infection control measures have played a major role in limiting human/camel-to-human transmissions, development of safe and effective human or camel vaccines is warranted. Here, we extended and optimized our previous rAd5-based vaccine platform characterized by in vivo amplified and CD40-mediated specific responses to generate MERS-CoV S1 subunit-based vaccine. We generated rAd5 constructs expressing CD40-targeted S1 fusion protein (rAd5-S1/F/CD40L), untargeted S1 (rAd5-S1), and GFP (rAd5-GFP), and evaluated their efficacy and safety in human DPP4 transgenic (hDPP4 Tg+) mice. Immunization of hDPP4 Tg+ mice showed that a single dose of rAd5-S1/F/CD40L elicited robust and significant specific IgG and neutralizing antibody responses as those induced in mice immunized with two-doses of rAd5-S1. After MERS-CoV challenge, both vaccines conferred complete protection against morbidity and mortality, as evidenced by significantly undetectable/reduced pulmonary viral loads as compared to control group. However, rAd5-S1 but not rAd5- S1/F/CD40L immunized mice exhibited marked pulmonary perivascular hemorrhage post MERS-CoV challenge despite the observed protection. Collectively, these data indicate that incorporating CD40L into this Ad5-based MERS-CoV S1 subunit vaccine as targeting molecule and molecular adjuvant can not only enhance immunogenicity and efficacy but also prevents induction of inadvertent pulmonary pathology in immunized and challenged mice, thereby offering a promising strategy to enhance the safety and potency of antigen-specific immune responses.
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Khan, W. I., Y. Motomura, P. A. Blennerhassett, H. Kanbayashi, A. K. Varghese, R. T. El-Sharkawy, J. Gauldie, and S. M. Collins. "Disruption of CD40-CD40 ligand pathway inhibits the development of intestinal muscle hypercontractility and protective immunity in nematode infection." American Journal of Physiology-Gastrointestinal and Liver Physiology 288, no. 1 (January 2005): G15—G22. http://dx.doi.org/10.1152/ajpgi.00159.2004.
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In our previous studies, we demonstrated that during Trichinella spiralis infection, T helper (Th) 2 cells contribute to the development of intestinal muscle hypercontractility and worm expulsion from the gut via STAT6. In addition, we have linked the altered muscle contractility to the eviction of the parasite and thereby to the host defense. However, the initial events linking infection to the development of muscle hypercontractility are poorly understood. In this study, we examined the contribution of CD40-CD40 ligand (CD40L) interaction in the development of intestinal muscle hypercontractility, in monocyte chemoattractant protein-1 (MCP-1) production, and in the Th2 response in CD40 ligand-deficient (CD40L −/−) mice infected with T. spiralis. Expulsion of intestinal worms was substantially delayed in CD40L −/− mice compared with the wild-type mice after T. spiralis infection. Consistent with delayed worm expulsion, there was a significant attenuation of intestinal muscle contractility in CD40L −/− mice. Infected CD40L −/− mice also exhibited marked impairment in the production of MCP-1, IL-4, IL-13, IgG1, IgE, and mouse mucosal MCP 1 (MMCP-1), and in goblet cell response. These results demonstrate that CD40-CD40 ligand interaction plays an important role in MCP-1 production, Th2 response, intestinal muscle hypercontractility, and worm expulsion in nematode infection. The present data suggest that the early events leading to the generation of Th2 response include CD40-CD40 ligand interaction, which subsequently influences the production of Th2 cytokines, most likely via upregulation of MCP-1.
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Kuang, Liang-Jian, Ting-Ting Deng, Qin Wang, Shi-Lin Qiu, Yi Liang, Zhi-Yi He, Jian-Quan Zhang, et al. "Dendritic cells induce Tc1 cell differentiation via the CD40/CD40L pathway in mice after exposure to cigarette smoke." American Journal of Physiology-Lung Cellular and Molecular Physiology 311, no. 3 (September 1, 2016): L581—L589. http://dx.doi.org/10.1152/ajplung.00002.2016.
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Dendritic cells and CD8+ T cells participate in the pathology of chronic obstructive pulmonary disease, including emphysema, but little is known of the involvement of the CD40/CD40L pathway. We investigated the role of the CD40/CD40L pathway in Tc1 cell differentiation induced by dendritic cells in a mouse model of emphysema, and in vitro. C57BL/6J wild-type and CD40−/− mice were exposed to cigarette smoke (CS) or not (control), for 24 wk. In vitro experiments involved wild-type and CD40−/− dendritic cells treated with CS extract (CSE) or not. Compared with the control groups, the CS mice (both wild type and CD40−/−) had a greater percentage of lung dendritic cells and higher levels of major histocompatability complex (MHC) class I molecules and costimulatory molecules CD40 and CD80. Relative to the CS CD40−/− mice, the CS wild type showed greater signs of lung damage and Tc1 cell differentiation. In vitro, the CSE-treated wild-type cells evidenced more cytokine release (IL-12/p70) and Tc1 cell differentiation than did the CSE-treated CD40−/− cells. Exposure to cigarette smoke increases the percentage of lung dendritic cells and promotes Tc1 cell differentiation via the CD40/CD40L pathway. Blocking the CD40/CD40L pathway may suppress development of emphysema in mice exposed to cigarette smoke.
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Ngaotepprutaram, Thitirat, Barbara L. F. Kaplan, Robert B. Crawford, and Norbert E. Kaminski. "Differential Modulation by Delta9-Tetrahydrocannabinol (∆9-THC) of CD40 Ligand (CD40L) Expression in Activated Mouse Splenic CD4+ T cells." Journal of Neuroimmune Pharmacology 7, no. 4 (August 1, 2012): 969–80. http://dx.doi.org/10.1007/s11481-012-9390-z.
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Lee, J. K., N. Seki, T. J. Sayers, J. Subleski, E. M. Gruys, W. J. Murphy, and R. H. Wiltrout. "Constitutive expression of functional CD40 on mouse renal cancer cells: Induction of Fas and Fas-mediated killing by CD40L." Cellular Immunology 235, no. 2 (June 2005): 145–52. http://dx.doi.org/10.1016/j.cellimm.2005.08.029.
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Chaussabel, Damien, Frédérique Jacobs, Jan de Jonge, Marijke de Veerman, Yves Carlier, Kris Thielemans, Michel Goldman, and Bernard Vray. "CD40 Ligation Prevents Trypanosoma cruziInfection through Interleukin-12 Upregulation." Infection and Immunity 67, no. 4 (April 1, 1999): 1929–34. http://dx.doi.org/10.1128/iai.67.4.1929-1934.1999.
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ABSTRACT Because of the critical role of the CD40-CD40 ligand (CD40L) pathway in the induction and effector phases of immune responses, we investigated the effects of CD40 ligation on the control ofTrypanosoma cruzi infection. First, we observed that supernatants of murine spleen cells stimulated by CD40L-transfected 3T3 fibroblasts (3T3-CD40L transfectants) prevent the infection of mouse peritoneal macrophages (MPM) by T. cruzi. This phenomenon depends on de novo production of nitric oxide (NO) as it is prevented by the addition of N-nitro-l-arginine methyl ester, a NO synthase inhibitor. NO production requires interleukin (IL)-12-mediated gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) synthesis as demonstrated by inhibition experiments using neutralizing anti-IL-12, anti-IFN-γ, and anti-TNF-α monoclonal antibodies (MAb). We found that an activating anti-CD40 MAb also directly stimulates IFN-γ-activated MPM to produce NO and thereby to control T. cruzi infection. To determine the in vivo relevance of these in vitro findings, mice were injected with 3T3-CD40L transfectants or 3T3 control fibroblasts at the time ofT. cruzi inoculation. We observed that in vivo CD40 ligation dramatically reduced both parasitemia and the mortality rate of T. cruzi-infected mice. A reduced parasitemia was still observed when the injection of 3T3-CD40L transfectants was delayed 8 days postinfection. It was abolished by injection of anti-IL-12 MAb. Taken together, these data establish that CD40 ligation facilitates the control of T. cruzi infection through a cascade involving IL-12, IFN-γ, and NO.