Articles de revues : « Human lymphocytes, regulatory RNAs, immune system »

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Haderk, Franziska, Etienne Moussay, Jerome Paggetti, Maria Göbel, Jan Dürig, Thorsten Zenz, Stephan Stilgenbauer, Peter Lichter et Martina Seiffert. « Chronic Lymphocytic Leukemia-Derived Extracellular Vesicles Contain a Distinctive Proteome, As Well As Specific Micro RNAs and Y RNAs ». Blood 124, n^o 21 (6 décembre 2014) : 1968. http://dx.doi.org/10.1182/blood.v124.21.1968.1968.

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Abstract The pathogenesis of chronic lymphocytic leukemia (CLL) is stringently associated with a tumor-supportive microenvironment and a dysfunctional immune system. Of note, CLL cells themselves induce changes in surrounding cells, and extracellular vesicles (EVs) released by CLL cells represent a newly discovered mechanism of cell-cell communication. EVs are membrane enclosed nanoparticles 30 to 1000 nm in size and are able to reprogram recipient cells by transferring proteins and RNA molecules from their cell of origin. Thus, we aimed to analyze CLL cell-derived EVs present in blood plasma of CLL patients as well as those released by the CLL cell line MEC-1, in order to understand their role within the microenvironment. EVs were isolated from blood plasma of CLL patients and healthy donors, as well as from MEC-1 cell culture supernatant by serial centrifugation and density-based separation. Characterization of EVs by electron microscopy and immunoblot analysis revealed vesicles 20 to 300 nm in size, which are positive for various EV marker proteins such as Rab5a and Hsp70. Proteome analysis via mass spectrometry indicated differences in the composition of plasma derived EVs and peripheral blood mononuclear cells (PBMCs) from the respective patient, as well as between plasma derived EVs from healthy donors compared to CLL patients. Regarding the later, CLL EVs were specifically enriched for proteins involved in antigen presentation, endocytosis signaling as well as integrin mediated signaling and leukocyte extravasation. RNA analysis by BioAnalyzer profiling indicated an enrichment of small RNAs in EVs compared to cells. Subsequent small RNA sequencing revealed a unique microRNA signature of MEC-1 EVs with the 5 most abundant miRNAs encompassing about 60% of all detected miRNAs. Among them, the CLL-relevant miR-21 and miR-155, as well as miR-146a were selectively enriched in EVs. Moreover, Y RNAs, another class of small non-coding, regulatory RNAs, were highly enriched in MEC-1 EVs and their presence was also observed in plasma EVs of CLL patients. We uncovered a rapid uptake of CLL cell-derived EVs by human monocytes and macrophages. Whether the identified proteins and RNA transcripts shown to be enriched in CLL EVs induce phenotypic changes in targeted cells is being investigated. Further, quantification of plasma EVs in a large cohort of CLL patients is currently conducted and differences in the amount of EVs in correlation to disease outcome are analyzed. Harboring a distinct RNA and protein profile, EVs are potent vehicles for shuttling RNA and proteins to recipient cells and might be involved in the establishment of a supportive microenvironment in CLL. Functional analyses regarding possible effects of CLL EVs on target cells will broaden the knowledge of CLL pathogenesis and might help to identify new therapeutic options for CLL. Disclosures No relevant conflicts of interest to declare.

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Silva, Priscilla Brito, Juliana Monte Real, Otavio C. G. Baiocchi, Gustavo Henrique Esteves, Joao Garibaldi Junior, Fabio Nascimento Brito, Adriana M. Damasco Penna, Egyla Cavalcante et Ludmila Rodrigues Pinto Ferreira. « Gene Networks and Canonical Pathways Analysis in Classical Hodgkin Lymphoma Patients ». Blood 128, n^o 22 (2 décembre 2016) : 5298. http://dx.doi.org/10.1182/blood.v128.22.5298.5298.

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Abstract Introduction: Molecular alterations involved in development of classical Hodgkin lymphoma (cHL) are only partially known. Genetic alterations in NFkB pathway and the imbalance of T regulatory (Treg) and TH17 lymphocytes has been recognized as critical pathogenetic mechanism involved in immune scape and blockade of apoptosis in Reed-Sternberg cells. Emerging evidences suggests that NFkB activation can promote lymphocyte proliferation and survival, and therapeutic inhibition of the NFkB pathway have been proposed. Recently, our group showed an increase of circulating Treg cells in patients with cHL at diagnosis, however, after therapy, elevated levels of circulating TH17 cells was observed. Increased frequencies of Treg lymphocytes in the tumor microenvironment and peripheral blood have been proposed as one of the mechanisms for this anergic state. TH17 exhibit effector functions in immune system and tumor-infiltrating TH17 cells are associated with better prognosis in human. Objectives: In this study we aimed to evaluate the immune gene expression profile in whole blood of cHL patients at diagnosis and after treatment, and evaluate pathways and gene interaction networks. Methods: This is an open multicenter study and, so far, we included 51 patients consecutively from February 2011 to November 2015. Twenty consecutively diagnosed cHL patients, with whole blood RNA extracted at diagnosis and after treatment, were recruited for this study and prospectively evaluated. All patients were HIV negative and received ABVD chemotherapy protocol and radiotherapy if necessary. The general expression of 96 messengers RNAs present in the peripheral blood and involved in immune response was performed by a customized quantitative real-time PCR array (TaqMan¨ Low Density Array). The data was normalized with B2M mRNAs levels and relative gene expression was calculated by the 2^DDCt method, considering Wilcoxon test and Benjamini-Hochberg adjustment to correct p-values. The differentially expressed genes were used to conduct functional/pathway enrichment analysis and construct gene interaction networks. Functional annotation networks were generated using Ingenuity Pathway Analysis (IPA; Ingenuity Systems) software. Results: From the 20 patients included for this study, 12 (60%) were male, 5 (31%) had Epstein Barr virus related cHL, 18 (90%) patients presented with B symptoms, 19 (95%) patients had advanced diseases at diagnosis (stage IIBX, III and IV) and 10% of patients relapsed. We considered paired samples from 15 patients before and after treatment. At diagnosis we observed that cHL patients presented higher expression of CD274 (2 fold, p=0.018), CD28 (1.5 fold, p=0.041), CTLA-4(1.5 fold, p=0.004), FAS (1.4 fold, p=0.041), ICOS (2.1 fold, p=0.015) and IL-10 (2.7 fold, p=0.002), and decreased expression of CCL2 (-2.7 fold, p=0.026), CCL5 (-1.6 fold, p=0.012), CD40 (-1.9 fold, p=0.003), CSF2 (-1.9 fold, p=0.012). We found no association between clinical and epidemiological characteristics with immune gene expression profile. We have found that after treatment, patients displayed a specific gene expression profile related to the top 5 canonical pathways summarized in following figure: We also built a biological network to investigate the connection between the differentially expressed genes and to predict the status (activation/inhibition) of the other connected genes (nodes). The in silico analysis revealed that NFkB, a node which its signaling activation is predicted to be activated before treatment and inhibited after (following figures). The network also showed different central node molecules (molecules connected with multiple other nodes from the network), that are indirectly related to Hodgkin lymphoma and should be further investigated as potential drugable targets. Conclusions: In this study, we showed that, at diagnosis, cHL patients presented an inflammatory gene expression profile in blood that changes after treatment to an effector/immunological one. NFkB is predicted to be activated before treatment and inhibited after ABVD chemotherapy and radiotherapy. This kind of system biology approach helped us to understand that cHL associated immunosuppression and the immune reconstitution after treatment maybe the key to develop new prognostic factors and treatment strategies as well as identify drugable targets. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures No relevant conflicts of interest to declare.

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Yokoyama, Kazuaki, Lu Jun, Takae Toyoshima, Hozumi Katsuto, Takashi Yahata, Kiyoshi Ando et Ai Kotani. « EBV-Specific Micro-RNA Via Exosome : A Key Inter-Cellular machinery between EBV+ Tumor and Tumor-Surrounding Immune Cells ? » Blood 120, n^o 21 (16 novembre 2012) : 50. http://dx.doi.org/10.1182/blood.v120.21.50.50.

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Abstract Abstract 50 The Epstein-Barr virus (EBV) is one of the most major human pathogen that establish long-term latent, or chronic infections, which is associated with a heterogeneous group of lymphoma, including Burkitt's lymphoma, Hodgkin's lymphoma (HL), NK-T lymphomas and lymphoproliferative disease. These malignancies are subdivided into in terms of EBV latent infection pattern, with typical three types of latency: type I to type III. HL is characterized by a minority of neoplastic Hodgkin and Reed-Sternberg (HRS), which are embedded in non-neoplastic bystanders, mostly B and T cells, but also macrophages. Without these bystander cells, these HL cells are incapable of being engrafted in immunodeficient mice. In this context, the non-tumor immune cells are tumor-supportive “inflammatory niche”. Because of the complexity of interplay between tumor and tumor surrounding immune cells, the detailed mechanism and how tumor cells escape from the attack of host immune cells remains an open question. Small RNAs including miRNAs are well known intra-cellular regulatory elements of gene expression. Recently, it was reported that they are conjugated in exosomes and transferred to cells and are involved in tumor metastasis by educating tumor surrounding niche. Moreover, it was also reported that EBV-infected lymphocytes produce exosomes that contain viral encoded, EBV specific miRNAs (BART-miRNA) and that these could be transferred in host cells and decrease the levels of known cellular targets. Accordingly, we hypothesized that EBV+ tumor derived exosomal BART-miRNA might redirect tumor surrounding immune cells from tumor reactive into tumor- -supportive “inflammatory niche”, which ultimately leads to tumor progression. To this aim, first, we evaluated tumor derived viral encoded BART-miRNA in EBV+HL clinical specimens by using BART-miRNA specific probe in situ hybridization. As expected, these EBV specific BART-miRNA could be detected in HRS as well as in tumor surrounding inflammatory niche, especially macrophage. This result indicated that tumor derived EBV specific BART-miRNA could transfer to the non-tumor cells in the tumor inflammatory niche, supporting the in vivo relevance of secretary EBV specific miRNA. Next, we evaluated the properties of exosomes produced by EBV+ cells (EBV-Ex). To this aim, EBV-Ex was harvested either from the media of the type III or type I EBV-transformed lymphoid cell line. Then, by using transwell co-culture system, we tested the delivery and the effect of EBV-Ex on human peripheral blood mononuclear cells (PBMC) derived monocyte/macrophage (Mo/Mf). As a result, we detected uptake of fluorochrome dye-labeled EBV-Exo in Mo/Mf. We also confirmed exosomal BART miRNA transfer in Mo/Mf. Surprisingly, exosome from Type III latency (Type III-Ex) was relatively enriched in BART miRNA, and were potent on Mo/Mf in inducing surface CD69 expression (Fig.A). This is in contrast to that of exosome from Type I latency (Type I-Ex), in which BART miRNA were relatively vacant and were weak in inducing surface CD69 expression (Fig.A). Panels of cytokine analysis by Q-PCR revealed that type III-Ex treated Mo/Mf displayed an anti-inflammatory/immunosuppressive cytokine rich signature, especially IL-10, compared to type I-Ex treated Mo/Mf, suggesting the possibility that type III-Ex might polarize macrophage into immunosuppressive M2-like phenotype. Intriguingly, type III-Ex from BART miRNA deletion mutant derivative cell lines totally lack the type III -Ex signature. Moreover, ectopic expression of a part of BART in Type I cells changed the EBV-Ex signature from type III to type I (Fig.B), suggesting the importance of specific BART lesion in functional EBV-Ex production in terms of Mo/Mf polarization. Taken these together, secretary tumor derived miRNAs in EBV associated malignancy, specifically in EBV+HL, might play a certain role in tumor inflammation niche. EBV might utilize the exosomal machinery to secrete key viral-encoded miRNAs, through which a small number of neoplastic EBV+ cells could modulate the tumor microenvironment. Disclosures: No relevant conflicts of interest to declare.

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Kechida, Melek. « Update on Autoimmune Diseases Pathogenesis ». Current Pharmaceutical Design 25, n^o 27 (9 octobre 2019) : 2947–52. http://dx.doi.org/10.2174/1381612825666190709205421.

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Background: Autoimmune diseases result from the interplay of cellular effectors like T and B cells, regulatory cells in addition to molecular factors like cytokines and regulatory molecules. Methods: Different electronic databases were searched in a non-systematic way to find out the literature of interest. Results: Pathogenesis of autoimmune diseases involves typical factors such as genetic background including HLA and non HLA system genes, environmental factors such as infectious agents and inflammatory cells mainly T and B lymphocytes abnormally activated leading to immune dysfunction. Other recently reported less typical factors such as micro-RNAs, circular RNAs, myeloperoxidase, vimentine and microbiome dysbiosis seem to be potential target therapies. Conclusion: We aimed in this manuscript to review common factors in the pathogenesis of autoimmune diseases.

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Xie, Yuhuai, et Yuanyuan Wei. « A Novel Regulatory Player in the Innate Immune System : Long Non-Coding RNAs ». International Journal of Molecular Sciences 22, n^o 17 (2 septembre 2021) : 9535. http://dx.doi.org/10.3390/ijms22179535.

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Long non-coding RNAs (lncRNAs) represent crucial transcriptional and post-transcriptional gene regulators during antimicrobial responses in the host innate immune system. Studies have shown that lncRNAs are expressed in a highly tissue- and cell-specific- manner and are involved in the differentiation and function of innate immune cells, as well as inflammatory and antiviral processes, through versatile molecular mechanisms. These lncRNAs function via the interactions with DNA, RNA, or protein in either cis or trans pattern, relying on their specific sequences or their transcriptions and processing. The dysregulation of lncRNA function is associated with various human non-infectious diseases, such as inflammatory bowel disease, cardiovascular diseases, and diabetes mellitus. Here, we provide an overview of the regulation and mechanisms of lncRNA function in the development and differentiation of innate immune cells, and during the activation or repression of innate immune responses. These elucidations might be beneficial for the development of therapeutic strategies targeting inflammatory and innate immune-mediated diseases.

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Ma, Yemei, Ying Ye, Yining Liu, Jing Chen, Yanli Cen, Wenyan Chen, Chun Yu, Qibing Zeng, Aihua Zhang et Guanghong Yang. « DNMT1-mediated Foxp3 gene promoter hypermethylation involved in immune dysfunction caused by arsenic in human lymphocytes ». Toxicology Research 9, n^o 4 (juillet 2020) : 519–29. http://dx.doi.org/10.1093/toxres/tfaa056.

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Abstract Growing evidence indicates that arsenic can cause long-lasting and irreversible damage to the function of the human immune system. It is known that forkhead box protein 3(Foxp3), which is specifically expressed in regulatory T cells (Tregs), plays a decisive role in immunoregulation and is regulated by DNA methylation. While evidence suggests that epigenetic regulated Foxp3 is involved in the immune disorders caused by arsenic exposure, the specific mechanism remains unclear. In this study, after primary human lymphocytes were treated with different doses of NaAsO2, our results showed that arsenic induced the high expression of DNMT1 and Foxp3 gene promoter methylation level, thereby inhibiting the expression levels of Foxp3, followed by decreasing Tregs and reducing related anti-inflammatory cytokines, such as interleukin 10 (IL-10) and interleukin 10 (IL-35), and increasing the ratio of CD4+/CD8+ T cells in lymphocytes. Treatment with DNA methyltransferase inhibitor 5-Aza-CdR can notably inhibit the expression of DNMT1, effectively restoring the hypermethylation of the Foxp3 promoter region in primary human lymphocytes and upregulating the expression levels of Foxp3, balancing the ratio of CD4+/CD8+ T cells in lymphocytes. It also activates the secretion of anti-inflammatory cytokines and restores the immune regulatory functions of Tregs. In conclusion, our study provides limited evidence that DNMT1-mediated Foxp3 gene promoter hypermethylation is involved in immune dysfunction caused by arsenic in primary human lymphocytes. The study can provide a scientific basis for further understanding the arsenic-induced immune dysfunction in primary human lymphocytes.

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Chirichella, Michele, Niccolò Bianchi, Emina Džafo, Elena Foli, Francesco Gualdrini, Amy Kenyon, Gioacchino Natoli et Silvia Monticelli. « RFX transcription factors control a miR-150/PDAP1 axis that restrains the proliferation of human T cells ». PLOS Biology 20, n^o 2 (10 février 2022) : e3001538. http://dx.doi.org/10.1371/journal.pbio.3001538.

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Within the immune system, microRNAs (miRNAs) exert key regulatory functions. However, what are the mRNA targets regulated by miRNAs and how miRNAs are transcriptionally regulated themselves remain for the most part unknown. We found that in primary human memory T helper lymphocytes, miR-150 was the most abundantly expressed miRNA, and its expression decreased drastically upon activation, suggesting regulatory roles. Constitutive MIR150 gene expression required the RFX family of transcription factors, and its activation-induced down-regulation was linked to their reduced expression. By performing miRNA pull-down and sequencing experiments, we identified PDGFA-associated protein 1 (PDAP1) as one main target of miR-150 in human T lymphocytes. PDAP1 acted as an RNA-binding protein (RBP), and its CRISPR/Cas-9–mediated deletion revealed that it prominently contributed to the regulation of T-cell proliferation. Overall, using an integrated approach involving quantitative analysis, unbiased genomics, and genome editing, we identified RFX factors, miR-150, and the PDAP1 RBP as the components of a regulatory axis that restrains proliferation of primary human T lymphocytes.

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Chen, J., J. Jiang, Y. Liu, Y. Ye, Y. Ma, Y. Cen, W. Chen, S. Wang, G. Yang et A. Zhang. « Arsenite induces dysfunction of regulatory T cells through acetylation control of the Foxp3 promoter ». Human & ; Experimental Toxicology 40, n^o 1 (31 juillet 2020) : 35–46. http://dx.doi.org/10.1177/0960327120934533.

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Arsenic is known to cause damage to the body’s immune system by inducing epigenetic changes. However, the molecular mechanism of this damage remains elusive. Here, we report that arsenic disrupts the morphology of lymphocytes, decreases cell viability, and results in abnormal proportions of T lymphocyte subsets. Moreover, our results revealed that arsenic can reduce global acetylation of histone H4 at K16 (H4K16 ac) in lymphocytes via decreasing the level of males absent on the first but upregulates mRNA and protein levels of the forkhead/winged-helix box P3 ( Foxp3) gene by increasing the acetylation of histone H4 at K16 (H4K16) at the promoter of Foxp3. Finally, arsenic-induced dysfunction of regulatory T cells (Tregs) could be ameliorated by trichostatin A. Our research indicates that arsenic-induced immunosuppressive effect in human lymphocytes may be related to the acetylation of H4K16 at the promoter of Foxp3 and that histone deacetylase inhibitors may play a role in the prevention and treatment of immune injury caused by arsenic.

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Loewendorf-Snead, Andrea, Tina Nguyen, Maria Yesayan et Daniel Kahn. « Uterine integrity is required to maintain human fetal immunologic naiveté (MUC7P.770) ». Journal of Immunology 192, n^o 1_Supplement (1 mai 2014) : 197.22. http://dx.doi.org/10.4049/jimmunol.192.supp.197.22.

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Abstract Introduction: In healthy pregnancy, maternal and fetal compartments are physically separated by multiple cell layers and the fetal immune system displays an ‘in-experienced’ phenotype in utero. The uterus as an immunologic barrier contributing to the naïve state of the fetal immune system has not been explored thus far. Methods: A prospective cohort study of fetuses born to mothers with prior uterine scar was undertaken (UCLA IRB # 11-002962). Cord blood lymphocytes were analyzed for memory status of the T regulatory cells (CD4+FoxP3+RO/RA) and blinded from placental location prior to final analysis. Results: In this prospective cohort study, we identified placental implantation in apposition to a uterine scar as a sufficient factor for fetal in utero immune activation (CD45RO+), specifically in the regulatory T cell compartment. Our results (N=20) identify a risk difference of 90% with a relative risk of 10 (p<0.05) of activation (RO+) of the FoxP3+ regulatory T cells when the placenta was implanted over the prior uterine scar. Discussion: Our study demonstrates that intrauterine formation of tolerogenic fetal responses is caused by fetal exposure to a scarred uterus. Our results highlight the role that uterine integrity plays as an immunologic barrier.

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Castro-Sánchez, Patricia, et José M. Martín-Villa. « Gut immune system and oral tolerance ». British Journal of Nutrition 109, S2 (29 janvier 2013) : S3—S11. http://dx.doi.org/10.1017/s0007114512005223.

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Gut mucosal surfaces separate the external environment from the internal sterile environment and so represent a first line of defence system. This barrier faces environments rich in pathogens that have developed effective mechanisms for colonisation of epithelial surfaces and invasion of mucosal tissues, but also harmless antigens such as food, airborne antigens or commensal bacterial flora. The latter represent the vast majority of the encountered antigens and require an appropriate response characterised by either ignorance or active suppression. However, for the former, a robust immune response is needed. Mucosae have developed a complex immune system that is capable of mounting an immune response against pathogenic antigens, while maintaining the required ignorance or active suppression against non-pathogenic antigens. Taking advantage of this knowledge, strategies have been devised to induce oral tolerance to antigens involved in experimental autoimmune disease or human conditions. It is now known that oral tolerance induces the up-regulation and activation of T cells with regulatory properties, a subtype of CD4+ T cells whose function is to regulate functions of other T lymphocytes to avoid excessive immune activation. Amongst them, the Th3 cells (cells that express the latency-associated peptide on the surface and secrete transforming growth factor β, a cytokine with immunoregulatory properties) are especially relevant in the induction of oral tolerance. Orally fed antigens seek to generate these types of cells in the treatment of autoimmune diseases in experimental animals or human subjects.

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Cheknev, S. B., Y. G. Ashmanova, A. D. Pritsker, O. L. Latysheva, F. I. Yershov et A. J. Kulberg. « Autologous Enhancement by Interferon of Natural Killer Activity of Human Peripheral Blood Lymphocytes ». Mediators of Inflammation 3, n^o 5 (1994) : 341–46. http://dx.doi.org/10.1155/s0962935194000475.

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Thein vitroaction of interferon (IFN)-α and IFN-γ from six healthy donors and ten patients with multiple sclerosis (MS) on natural killer (INK) activity of peripheral blood lymphocytes (PBL) was studied in an autologous system. The NK activity of PBL was detected by a cytotoxic test using3H-uridine human erythromyeloblast K562 cells. Autologous IFN-α and IFN-γ did not augment NK activity of PBL from healthy donorsin vitro, whereas in samples from MS patients the IFNs strongly stimulated NK cell cytotoxic function. This stimulation suggests the existence of an inhibitor of regulatory IFN action, that is produced in healthy donors simultaneously with IFN in response to IFN induction, but which is lacking in commercial IFN preparations. The factor-containing supernatants from healthy donors reduced the stimulatory action of autologous IFNs in patients with MS almost until complete blockade. Because this inhibitor was absent in patients with MS, deficiency of an inhibitor of IFN regulatory action in MS could open the way to treatment of this compartment of the immune system.

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Grossman, William J., James W. Verbsky, Benjamin L. Tollefsen, Claudia Kemper, John P. Atkinson et Timothy J. Ley. « Differential expression of granzymes A and B in human cytotoxic lymphocyte subsets and T regulatory cells ». Blood 104, n^o 9 (1 novembre 2004) : 2840–48. http://dx.doi.org/10.1182/blood-2004-03-0859.

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Abstract Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells use the perforin/granzyme pathway as a major mechanism to kill pathogen-containing cells and tumor cells.1,2 Dysregulation of this pathway results in several human diseases, such as hemophagocytic lymphohistiocytosis. Here we characterize the single-cell expression pattern of granzymes A and B in human lymphocytes using a flow cytometry-based assay. We demonstrate that most circulating CD56+8- NK cells, and approximately half of circulating CD8+ T lymphocytes, coexpressed both granzymes A and B. In contrast, few circulating CD4+ T lymphocytes expressed granzymes A or B. Activation of CD8+ T lymphocytes with concanavalin A (ConA)/interleukin-2 (IL-2), and activation of CD4+ T lymphocytes with antibodies to CD3/CD28 or CD3/CD46 (to generate T regulatory [Tr1] cells), induced substantial expression of granzyme B, but not granzyme A. Naive CD4+CD45RA+ cells stimulated with antibodies to CD3/CD46 strongly expressed granzyme B, while CD3/CD28 stimulation was ineffective. Finally, we show that granzyme B-expressing CD4+ Tr1 cells are capable of killing target cells in a perforin-dependent, but major histocompatibility complex (MHC)/T-cell receptor (TCR)-independent, manner. Our results demonstrate discordant expression of granzymes A and B in human lymphocyte subsets and T regulatory cells, which suggests that different granzymes may play unique roles in immune system responses and regulation.

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Mukherji, B., A. L. Nashed, A. Guha et M. T. Ergin. « Regulation of cellular immune response against autologous human melanoma. II. Mechanism of induction and specificity of suppression. » Journal of Immunology 136, n^o 5 (1 mars 1986) : 1893–98. http://dx.doi.org/10.4049/jimmunol.136.5.1893.

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Abstract The cytotoxic immune response in the peripheral blood lymphocytes (PBL) against an autologous malignant melanoma cell line, PJ-M, was found to be down-regulated in in vitro co-culture (IVC) selectively by unfractionated resident lymph node lymphocytes (derived from a lymph node infiltrated with the PJ-M melanoma cells) and T4+ as well as T8+ fractions of the resident lymph node-derived lymphocytes. In this study, the mechanism involved in, and the specificities of, cytotoxic immune response in this autologous system were examined at population and clonal levels. Resident lymph node lymphocytes were isolated from both involved and uninvolved lymph nodes from the same patient. Resident lymphocytes from both sources regulated the generation of cytotoxic immune response when both types of resident lymph node lymphocytes were further sensitized against the PJ-M cells in IVC and were expanded in interleukin 2 (IL 2). An IL 2-dependent homogeneous lymphocyte line (I-10:1) bearing the phenotype of a helper T cell (T4+) and a T4+ clone (I-10.3) of the I-10:1 line, established by limiting dilution culture, also down-regulated the generation of cytotoxic immune effector cells in the PBL in IVC against the PJ-M targets. The IL 2-dependent T4+ inducer line I-10:1 generated a functionally differentiated T8+ suppressor population(s) that, in turn, could abrogate cytotoxic response in fresh PBL in IVC against PJ-M cells. The inducer line I-10:1 and its subclone I-10.3 suppressed the generation of cytotoxic effector cells in the PBL in IVC selectively against the autologous PJ-M cells. Generation of cytotoxic allo-response in IVC was unaffected by the inducer lines. These results provide further evidence for the involvement of the regulatory network in cytotoxic immune response in an autologous human tumor system, and suggest a potential explanation for cytotoxic unresponsiveness against autologous melanoma cells.

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Kumagai-Takei, Naoko, Suni Lee, Bandaru Srinivas, Yurika Shimizu, Nagisa Sada, Kei Yoshitome, Tatsuo Ito, Yasumitsu Nishimura et Takemi Otsuki. « The Effects of Asbestos Fibers on Human T Cells ». International Journal of Molecular Sciences 21, n^o 19 (23 septembre 2020) : 6987. http://dx.doi.org/10.3390/ijms21196987.

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Asbestos exposure causes malignant tumors such as lung cancer and malignant mesothelioma. The effects of asbestos fibers on immunocompetent cells, however, have not been well studied. Asbestos physically comprises a fibrous substance, which differs from silica particles which are a particulate substance, although chemically it is a mineral silicate. Since silicosis patients previously exposed to silica particles often suffer from lung and autoimmune diseases, it is clear that silica exposure impairs immune tolerance. Similarly, asbestos may alter the immune system in asbestos-exposed individuals. Given that malignant tumors can result following exposure to asbestos, the attenuation of anti-tumor immunity in cases of asbestos exposure is an important area of investigation. We observed the effect of asbestos fibers on T lymphocytes, such as CD8+ cytotoxic T lymphocytes (CTLs), CD4+ helper T (Th), and regulatory T (Treg) cells, and showed that anti-tumor immunity was attenuated, as demonstrated in a system that stimulates fresh cells isolated from peripheral blood in vitro and a system that is continuously exposed to a cell line. In this manuscript, we introduce the experiments and results of studies on CTLs, as well as Th and Treg cells, and discuss how future changes in immunocompetent cells induced by asbestos fibers can be clinically linked.

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Novikov, V. V., V. A. Lapin, D. A. Melentiev et E. V. Mokhonova. « Features of the human immune response to Helicobacter pylori infection ». MediAl, n^o 2 (15 décembre 2019) : 55–69. http://dx.doi.org/10.21145/2225-0026-2019-2-55-69.

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Helicobacter pylori is considered the etiological agent of acute and chronic forms of gastritis, and is also capable of exerting a multifactorial effect on the host organism and on the nature of the immune response. The inflammatory response to H. pylori infection has its own characteristics. With an active course, inflammatory reactions, when the modulating effect of regulatory T-lymphocytes (T-reg) is weakened and populations of pro-inflammatory cells (T-helpers 1, 17, 22 type and follicular T-helpers) are activated, which have pronounced destructive changes in the gastric mucosa and the duodenum. guts. Macrophages, dendritic cells and neutrophils are cellular factors of the innate immune system, as well as adaptive immunity, which provides protection against infection. In turn, H. pylori uses a variety of mechanisms to evade the destruction of the host immune system. Long-term preservation of inflammation can cause local activation of mutagenesis, which initiates the development of malignant neoplasms of the gastric mucosa. A review of the host immune response to H. pylori is devoted to this analytical review.

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Cuellar, Trinna L., Anna-Maria Herzner, Xiaotian Zhang, Yogesh Goyal, Colin Watanabe, Brad A. Friedman, Vasantharajan Janakiraman et al. « Silencing of retrotransposons by SETDB1 inhibits the interferon response in acute myeloid leukemia ». Journal of Cell Biology 216, n^o 11 (8 septembre 2017) : 3535–49. http://dx.doi.org/10.1083/jcb.201612160.

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A propensity for rewiring genetic and epigenetic regulatory networks, thus enabling sustained cell proliferation, suppression of apoptosis, and the ability to evade the immune system, is vital to cancer cell propagation. An increased understanding of how this is achieved is critical for identifying or improving therapeutic interventions. In this study, using acute myeloid leukemia (AML) human cell lines and a custom CRISPR/Cas9 screening platform, we identify the H3K9 methyltransferase SETDB1 as a novel, negative regulator of innate immunity. SETDB1 is overexpressed in many cancers, and loss of this gene in AML cells triggers desilencing of retrotransposable elements that leads to the production of double-stranded RNAs (dsRNAs). This is coincident with induction of a type I interferon response and apoptosis through the dsRNA-sensing pathway. Collectively, our findings establish a unique gene regulatory axis that cancer cells can exploit to circumvent the immune system.

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Arneth, Borros M. « Activation of CD4 and CD8 T cell receptors and regulatory T cells in response to human proteins ». PeerJ 6 (9 mars 2018) : e4462. http://dx.doi.org/10.7717/peerj.4462.

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This study assessed in detail the influence of four different human proteins on the activation of CD4+ and CD8+ T lymphocytes and on the formation of regulatory T cells. Human whole-blood samples were incubated with four different human proteins. The effects of these proteins on the downstream immune-system response, on the expression of extracellular activation markers on and intracellular cytokines in T lymphocytes, and on the number of regulatory T cells (T-reg cells) were investigated via flow cytometry. Incubation with β-actin or glyceraldehyde 3-phosphate dehydrogenase (GAPDH), which are cytoplasmic proteins, increased the expression of both extracellular activation markers (CD69 and HLA-DR) and intracellular cytokines but did not significantly affect the number of T-reg cells. In contrast, incubation with human albumin or insulin, which are serum proteins, reduced both extracellular activation markers and intracellular cytokine expression and subsequently increased the number of T-reg cells. These findings may help to explain the etiological basis of autoimmune diseases.

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Du, Jianguang, Qun Wang, Lina Wang et Baohua Zhou. « Exon 2 of Foxp3 contributes to the peripheral tolerance of the immune system ». Journal of Immunology 196, n^o 1_Supplement (1 mai 2016) : 191.23. http://dx.doi.org/10.4049/jimmunol.196.supp.191.23.

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Abstract Foxp3 is essential for the development and function of CD4 regulatory T cells (Tregs) that maintain peripheral immune tolerance. A major difference of Foxp3 expression between human and mouse is the alternative splicing of exon 2 in human Tregs. In vitro studies showed that the exon 2 region of Foxp3 associates and inhibits the transcription factors RORα and RORγt, which are critical for Th17 differentiation. However the in vivo role of exon 2 is still unknown. By deleting exon 2 of mouse Foxp3 gene (dE2), we show here that peripheral and mesenteric lymph nodes of dE2 mice contained about twice amount of lymphocytes when compared with wildtype mice due to the higher level of CD4 T cell activation and proliferation. Exon 2 deletion resulted in more severe air way inflammation in OVA-induced chronic asthma, characterized by higher number of lymphocytes and eosinophils in bronchoalveolar lavage, and high level of OVA-specific serum IgE. CD4 T cells in the mediastinal lymph nodes of dE2 mice expressed higher IL-4, IL-9 and IFN-γ, but surprisingly not IL-17, compared with those in wild type mice. These data indicate that Foxp3 exon 2 is important in maintaining proper functions of peripheral Tregs, and thus contributes to the peripheral tolerance to dampen allergic inflammation against harmless antigens.

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Cho, Sunglim, Jesse W. Tai et Li-Fan Lu. « MicroRNAs and Their Targetomes in Tumor-Immune Communication ». Cancers 12, n^o 8 (24 juillet 2020) : 2025. http://dx.doi.org/10.3390/cancers12082025.

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The development of cancer is a complex and dynamically regulated multiple-step process that involves many changes in gene expression. Over the last decade, microRNAs (miRNAs), a class of short regulatory non-coding RNAs, have emerged as key molecular effectors and regulators of tumorigenesis. While aberrant expression of miRNAs or dysregulated miRNA-mediated gene regulation in tumor cells have been shown to be capable of directly promoting or inhibiting tumorigenesis, considering the well-reported role of the immune system in cancer, tumor-derived miRNAs could also impact tumor growth through regulating anti-tumor immune responses. Here, we discuss howmiRNAs can function as central mediators that influence the crosstalk between cancer and the immune system. Moreover, we also review the current progress in the development of novel experimental approaches for miRNA target identification that will facilitate our understanding of miRNA-mediated gene regulation in not only human malignancies, but also in other genetic disorders.

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Rodriguez-Iturbe, Bernardo, Hector Pons et Richard J. Johnson. « Role of the Immune System in Hypertension ». Physiological Reviews 97, n^o 3 (1 juillet 2017) : 1127–64. http://dx.doi.org/10.1152/physrev.00031.2016.

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High blood pressure is present in more than one billion adults worldwide and is the most important modifiable risk factor of death resulting from cardiovascular disease. While many factors contribute to the pathogenesis of hypertension, a role of the immune system has been firmly established by a large number of investigations from many laboratories around the world. Immunosuppressive drugs and inhibition of individual cytokines prevent or ameliorate experimental hypertension, and studies in genetically-modified mouse strains have demonstrated that lymphocytes are necessary participants in the development of hypertension and in hypertensive organ injury. Furthermore, immune reactivity may be the driving force of hypertension in autoimmune diseases. Infiltration of immune cells, oxidative stress, and stimulation of the intrarenal angiotensin system are induced by activation of the innate and adaptive immunity. High blood pressure results from the combined effects of inflammation-induced impairment in the pressure natriuresis relationship, dysfunctional vascular relaxation, and overactivity of the sympathetic nervous system. Imbalances between proinflammatory effector responses and anti-inflammatory responses of regulatory T cells to a large extent determine the severity of inflammation. Experimental and human studies have uncovered autoantigens (isoketal-modified proteins and heat shock protein 70) of potential clinical relevance. Further investigations on the immune reactivity in hypertension may result in the identification of new strategies for the treatment of the disease.

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Herbstritt, Anna, Elfriede Noessner, Petra Prinz, Mani Kadiyala, Melissa Maxwell, Dingxue Yan, James Cardia et Simon Fricker. « 599 New checkpoints controlling function of cytotoxic lymphocytes infiltrating human carcinoma ». Journal for ImmunoTherapy of Cancer 8, Suppl 3 (novembre 2020) : A634. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0599.

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BackgroundAlthough present in high numbers, T and NK cells appear functionally impaired in the renal cell carcinoma (RCC) tumor milieu, as they cannot be stimulated to degranulation and IFN-γ production. This is in part due to altered regulation of signaling downstream of the T cell receptor (TCR). Increased diacylglycerol kinase alpha (DGK-α) has been observed in T and NK cells from the RCC tumor microenvironment (TME). Ex vivo inhibition of DGK-α by the commercially available inhibitor R59022 was able to restore responsiveness to stimulation.1 2 Inhibition of DGK-α is reported to also block tumor cell growth and survival.3 4 Many T cells from RCC additionally express the immune checkpoint Programmed cell Death-1 (PD-1). Interaction of PD-1 with PD-L1 on tumor cells blocks AKT signaling and inhibits T cell function. In the clinic, blocking the PD-1/PD-L1 interaction allows tumor control in some patients; however, the majority of patients do not respond long-term. Since DGK-α acts downstream of PD-1 it may, if overactive, curb T cell function despite PD-1/PD-L1 blockade. Thus, we hypothesize that dual inhibition of PD-1 and DGK α might be required to fully unleash the T cell’s potential in the TME.Current DGK-α inhibitors are not suitable for clinical application. Therefore, we investigate alternative means using RNA interference (RNAi) to target DGK-α alone as well as in combination with PD-1.MethodsKnockdown was achieved by RNAi using INTASYLTM compounds, developed by Phio Pharmaceuticals. These compounds incorporate drug-like properties into siRNA, resulting in enhanced uptake with no need for transfection reagents. Efficacy was analyzed on mRNA and protein level by rt-qPCR, flow cytometry and Western Blot. Functional assays include cytotoxicity and cytokine production in tumor-mimicking environments.ResultsUsing INTASYLTM compounds, silencing of DGK-α was observed in human U2OS osteosarcoma as well as K562 erythroleukemic cells. PD-1 knockdown was achieved in human T cells isolated from peripheral blood mononuclear cells (PBMC). Synergy of DGK-α and PD-1 knockdown is tested in tumor-mimicking in vitro systems using T cell/tumor cell co-cultures at high tumor cell density where T and NK cells become functional suppressed as observed in the TME.ConclusionsStrong activity of specific T and NK cells is necessary for tumor control. Dual targeting of PD-1 and DGK-α may be required to fully enable T and NK cell reactivity in the TME. Self-delivering RNAi technology represents a promising approach to targeting intracellular immune checkpoints such as DGK-α, in addition to PD-1 inhibition.ReferencesPrinz PU, Mendler AN, Masouris I, Durner L, Oberneder R, Noessner E. High DGK-α and disabled MAPK pathways cause dysfunction of human tumor-infiltrating CD8+ T cells that is reversible by pharmacologic intervention. J Immunol 2012 Jun 15;188(12):5990–6000. doi: 10.4049/jimmunol.1103028. Epub 2012 May 9. PMID: 22573804.Prinz PU, Mendler AN, Brech D, Masouris I, Oberneder R, Noessner E. NK-cell dysfunction in human renal carcinoma reveals diacylglycerol kinase as key regulator and target for therapeutic intervention. Int J Cancer 2014 Oct 15;135(8):1832–41. doi: 10.1002/ijc.28837. Epub 2014 Mar 26. PMID: 24615391.Torres-Ayuso P, Daza-Martín M, Martín-Pérez J, Ávila-Flores A, Mérida I. Diacylglycerol kinase α promotes 3D cancer cell growth and limits drug sensitivity through functional interaction with Src. Oncotarget 2014 Oct 30;5(20):9710–26. doi: 10.18632/oncotarget.2344. PMID: 25339152; PMCID: PMC4259432.Yanagisawa K, Yasuda S, Kai M, Imai S, Yamada K, Yamashita T, Jimbow K, Kanoh H, Sakane F. Diacylglycerol kinase alpha suppresses tumor necrosis factor-alpha-induced apoptosis of human melanoma cells through NF-kappaB activation. Biochim Biophys Acta 2007 Apr; 1771(4):462–74. doi: 10.1016/j.bbalip.2006.12.008. Epub 2007 Jan 8. PMID: 17276726.

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Oleinik, E. K., A. V. Churov et V. M. Oleinik. « IMMUNOLOGICAL MEMORY : THE ROLE OF REGULATORY CELLS (TREGS) ». Medical Immunology (Russia) 20, n^o 5 (6 novembre 2018) : 613–20. http://dx.doi.org/10.15789/1563-0625-2018-5-613-620.

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Memory T cells are necessary for development of the immune response and represent one of the most numerous population of human T lymphocytes. On the contrary, suppressive regulatory T cells (Tregs) may terminate the immune response and help to maintain tolerance to self-antigens. These important groups of cells are consisting of different subpopulations and retaining throughout life. However, today there is yet no clear understanding of how the relations between these two groups of cells are formed. In this work we consider possible ways of development and maintenance of CD4+ T cell memory and role of Tregs in these processes. Mechanisms of a differentiation of memory T cells, Tregs and recently described memory Tregs are discussed. The functional and genetic characteristics of these cells are compared. Division of cells according to the functional profile allows drawing parallels between memory T cells and Tregs. These two groups are consisted of central circulating populations (Tc), effector which can migrate toward specific tissues (Te) and tissue-resident cells (Tr), which are staying in peripheral tissues. The similar structural organization of Tregs and memory T cells, existence of transitional forms of tissue-resident Treg subpopulations with properties of memory cells assumes existence of close interrelation between these groups of lymphocytes. The conversion of CD4+ memory T cells into FoxP3-expressing Tregs is one of possible mechanisms of communication between these two groups. The memory Treg-cells with T cell and memory Treg-cell properties can represent a transitional stage of differentiation. On the other side, Treg cells can differentiate independently of memory T cells and accumulate during life in the form of memory Treg cells. The supressor function of Tregs is also necessary as well as function of memory T cells to develop the immune response. It is possible, that a subset of Treg cells undergoes selection in thymus and constitutively express TCR-receptors having affinity with peripheral tissues. Further, these committed cells can be settled into tissues and become tissue-resident Treg cells which maintain regional T cell memory. Tregs can represent the “mirror image” of the structural organization of memory T cells, but with the return sign – the sign of suppression. The quantitative ratio of Tregs and memory T cells (CD4+CD45RO+CD25hiFoxP3+/CD4+CD45RO+CD25-FoxP3-), perhaps, is important criterion for functional assessment of immune system. The balance between these functionally opposite cell subsets has to provide stable functioning of immune system.

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He, Yingying, Zhicheng He, Serena Leone et Shubai Liu. « Milk Exosomes Transfer Oligosaccharides into Macrophages to Modulate Immunity and Attenuate Adherent-Invasive E. coli (AIEC) Infection ». Nutrients 13, n^o 9 (14 septembre 2021) : 3198. http://dx.doi.org/10.3390/nu13093198.

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Exosomes are abundance in human body fluids like urine, milk and blood. They act a critical role in extracellular and intracellular communication, intracellular trafficking and physiological regulation. Multiple immune-modulatory components, such as proteins, RNAs and carbohydrates (glycoproteins), have been found in human milk exosomes, which play immune-regulatory functions. However, little is known about oligosaccharides in milk exosomes, the “free sugars”, which act critical roles in the development of infant’s immature mucosal immune system. In this study, the profile of milk exosomes encapsulated human milk oligosaccharides (HMOs) was calibrated with characteristic oligosaccharides in colostrum and mature milk, respectively. The exosomes containing human milk oligosaccharides were uptaken by macrophages, which were responsible for the establishment of intestinal immunity. Furthermore, mice pretreated with exosome encapsulated HMOs were protected from AIEC infection and had significantly less LPS-induced inflammation and intestinal damage. Exosome encapsulated milk oligosaccharides are regarded to provide a natural manner for milk oligosaccharides to accomplish their critical functions in modifying newborn innate immunity. The understanding of the interaction between a mother’s breastfeeding and the development of an infant’s mucosal immune system would be advantageous. The transport of milk oligosaccharides to its target via exosome-like particles appears to be promising.

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Yegutkin, Gennady G., Kaisa Auvinen, Marika Karikoski, Pia Rantakari, Heidi Gerke, Kati Elima, Mikael Maksimow et al. « Consequences of the Lack of CD73 and Prostatic Acid Phosphatase in the Lymphoid Organs ». Mediators of Inflammation 2014 (2014) : 1–10. http://dx.doi.org/10.1155/2014/485743.

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CD73, ecto-5′-nucleotidase, is the key enzyme catalyzing the conversion of extracellular AMP to adenosine that controls vascular permeability and immunosuppression. Also prostatic acid phosphatase (PAP) possesses ecto-5′-nucleotidase/AMPase activity and is present in leukocytes. However, its role related to immune system is unknown. Therefore, we analyzed enzymatic activities and leukocyte subtypes of CD73 and PAP knockouts and generated CD73/PAP double knockout mice to elucidate the contribution of CD73 and PAP to immunological parameters. Enzymatic assays confirmed the ability of recombinant human PAP to hydrolyze [3H]AMP, although at much lower rate than human CD73. Nevertheless, 5′-nucleotidase/AMPase activity in splenocytes and lymphocytes from PAP−/−mice tended to be lower than in wild-type controls, suggesting potential contribution of PAP, along with CD73, into lymphoid AMP metabolism ex vivo. Single knockouts had decreased number ofCD4+/CD25+/FoxP3+regulatory T cells in thymus and CD73/PAP double knockouts exhibited reduced percentages of CD4+cells in spleen, regulatory T cells in lymph nodes and thymus, and CD4+and CD8+cells in blood. These findings suggest that PAP has a synergistic role together with CD73 in the immune system by contributing to the balance of leukocyte subpopulations and especially to the number of regulatory T cells in lymph nodes and thymus.

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Lechien, Jérôme R., Géraldine Descamps, Imelda Seminerio, Sonia Furgiuele, Didier Dequanter, Francois Mouawad, Cécile Badoual, Fabrice Journe et Sven Saussez. « HPV Involvement in the Tumor Microenvironment and Immune Treatment in Head and Neck Squamous Cell Carcinomas ». Cancers 12, n^o 5 (25 avril 2020) : 1060. http://dx.doi.org/10.3390/cancers12051060.

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Head and neck squamous cell carcinomas (HNSCC) are one of the most prevalent cancers worldwide. Active human papillomavirus (HPV) infection has been identified as an important additional risk factor and seems to be associated with a better prognosis in non-drinker and non-smoker young patients with oropharyngeal SCC. The better response of the immune system against the HPV-induced HNSCC is suspected as a potential explanation for the better prognosis of young patients. To further assess this hypothesis, our review aims to shed light the current knowledge about the impact of HPV infection on the immune response in the context of HNSCC, focusing on the innate immune system, particularly highlighting the role of macrophages, Langerhans and myeloid cells, and on the adaptative immune system, pointing out the involvement of T regulatory, T CD8 and T CD4 lymphocytes. In addition, we also review the preventive (HPV vaccines) and therapeutic (checkpoint inhibitors) strategies against HPV-related HNSCC, stressing the use of anti-CTLA4, PD-L1, PD-L2 antibodies alone and in combination with other agents able to modulate immune responses.

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Koralnik, Igor J., Renaud A. Du Pasquier et Norman L. Letvin. « JC Virus-Specific Cytotoxic T Lymphocytes in Individuals with Progressive Multifocal Leukoencephalopathy ». Journal of Virology 75, n^o 7 (1 avril 2001) : 3483–87. http://dx.doi.org/10.1128/jvi.75.7.3483-3487.2001.

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ABSTRACT Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by a reactivation of the polyomavirus JC (JCV) within a setting of immunosuppression. The nature of the immune response that contains replication of this virus is unknown. We have explored JCV-specific cellular immune responses in patients with PML and control subjects. JCV antigen-stimulated peripheral blood mononuclear cells (PBMC) of four human immunodeficiency virus (HIV)-infected patients who were survivors of PML and one HIV-uninfected patient recently diagnosed with PML lysed autologous B-lymphoblastoid cell lines expressing either the JCV T regulatory protein or the VP1 major capsid protein. This lysis was mediated by CD8+ T lymphocytes and was major histocompatibility complex class I restricted. These cells were therefore cytotoxic T lymphocytes (CTL). JCV-specific CTL could not be detected in PBMC of three HIV-infected PML patients who had progressive neurologic disease and an eventual fatal outcome. These data suggest that the JCV-specific cellular immune response may play a crucial role in the containment of PML. This finding may also prove useful as a favorable prognostic marker in the clinical management of these patients.

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Wagner, N., P. Engel et T. F. Tedder. « Regulation of the tyrosine kinase-dependent adhesion pathway in human lymphocytes through CD45. » Journal of Immunology 150, n^o 11 (1 juin 1993) : 4887–99. http://dx.doi.org/10.4049/jimmunol.150.11.4887.

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Abstract Cell-cell adhesive interactions involve numerous receptor/ligand interactions that play a crucial role in the development of immune function. Engagement of multiple cell-surface molecules on B lymphocytes generates intracellular signals through a tyrosine kinase-dependent pathway that activates cell-surface adhesion receptors and thereby induces homotypic cell-cell adhesion. Homotypic adhesion is mediated in part through LFA-1/ICAM-1 and other heretofore unknown adhesion receptors. In this study, evidence of a regulatory role for CD45 in the induction of homotypic adhesion is suggested. A new mAb (HAB-1) was developed that inhibits homotypic adhesion in B cell lines induced through MHC class I and class II, CD19, CD20, CD21, CD40, and Leu-13 cell-surface molecules. Although binding of this mAb strongly inhibited cell-surface Ag-induced homotypic adhesion at mAb concentrations as low as 0.1 microgram/ml, it exhibited no effect on homotypic adhesion induced by phorbol esters. Binding of the HAB-1 mAb to lymphocytes altered the pattern of cellular protein tyrosine phosphorylation, but did not have a global inhibitory effect on cell activation because it did not have major effects on the growth of mitogen-activated lymphocytes. Immunoprecipitation studies revealed that the HAB-1 mAb identified an epitope present on all isoforms of CD45. The HAB-1 mAb may identify a unique epitope of CD45 because this mAb had a unique staining pattern when assessed by indirect immunofluorescence staining. The HAB-1 mAb was similar to some other CD45 mAb that have the capacity to amplify CD2-induced proliferation of blood lymphocytes. However, only 1 of 12 other anti-CD45 mAb tested had a similar inhibitory effect on adhesion. Homotypic adhesion of lymphocytes may therefore be governed by a regulatory system of cell-surface molecules that generate positive and negative signals that either trigger adhesion or, like CD45, directly down-regulate adhesion. This highlights the significance of adhesive events that result from surface molecules being engaged by their natural ligands during lymphocyte activation.

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Fu, Liu, Zhe Wang, Fengxiang Jiang, Guohua Wei, Longe Sun, Chuanyong Guo, Jianye Wu et Jianhuan Zhu. « High Expression of EIF4G2 Mediated by the TUG1/Hsa-miR-26a-5p Axis Is Associated with Poor Prognosis and Immune Infiltration of Gastric Cancer ». Journal of Oncology 2022 (16 septembre 2022) : 1–25. http://dx.doi.org/10.1155/2022/9342283.

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Objective. Eukaryotic translation initiation factor 4 gamma 2 (EIF4G2) is involved in the occurrence and development of various tumors. However, the effect of EIF4G2 in gastric cancer (GC) has not been fully explored. The purpose of this study was to explore the function and mechanism of EIF4G2 in GC. Methods. The Tumor Immune Estimation Resource 2.0 database was used to analyze EIF4G2 expression in various cancers and the relationship between EIF4G2 expression and tumor-infiltrating immune cells. Gene Expression Profiling Interactive Analysis was utilized to assess the EIF4G2 expression level and its effect on survival in GC. UALCAN was conducted to analyze EIF4G2 expression in various subgroups of GC. The Kaplan–Meier plotter was employed for survival analysis. Receiver operator characteristic (ROC) curve analysis was applied to evaluate the diagnostic role of EIF4G2 in GC. LinkedOmics was used to identify the co-expressed genes and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways. The Tumor-Immune System Interaction database was employed to analyze the correlation between EIF4G2 expression and tumor-infiltrating lymphocytes. The starBase web platform was used to predict the upstream microRNAs and long noncoding RNAs. Results. EIF4G2 expression was upregulated in GC tissues compared to normal controls. High expression of EIF4G2 indicated poor prognosis in GC. ROC analysis revealed that EIF4G2 had good diagnostic ability to distinguish GC from normal tissues. Immune infiltration analysis indicated that EIF4G2 expression may be involved in the modulation of tumor immune infiltration in GC. Finally, we determined that the Taurine Upregulated 1 (TUG1)/hsa-miR-26a-5p/EIF4G2 axis was the most likely regulatory pathway involved in GC development. Conclusions. EIF4G2 was upregulated in GC and elevated expression of EIF4G2 indicated unfavorable prognosis. Moreover, EIF4G2 expression may be involved in the regulation of tumor immune cell infiltration. The TUG1/hsa-miR-26a-5p axis is a likely upstream regulatory mechanism of EIF4G2 in GC. EIF4G2 may thus serve as a prognosis biomarker and present a new therapeutic target.

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Kretz-Rommel, A., N. Dakappagari, F. Qin, J. McWhirter, D. Oltean, E. Ravey, D. Wu, J. Springhorn, A. Saven et K. Bowdish. « Immune evasion by CD200 : New approaches to targeted therapies for chronic lymphocytic leukemia (CLL) ». Journal of Clinical Oncology 24, n^o 18_suppl (20 juin 2006) : 2519. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.2519.

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2519 Background: Although the human immune system is capable of raising an immune response against many cancer types, that response is insufficient to eradicate the cancer in most patients, possibly due to immune evasion through negative regulation of the immune system by the tumor. We identified the immune-suppressive molecule CD200 to be upregulated 1.5–5.4-fold on CLL cells in all 80 patients examined. Interaction of CD200 with its receptor alters cytokine profiles from Th1 to Th2 in mixed lymphocyte reactions, and results in the induction of regulatory T cells, which are thought to hamper tumor-specific effector T cell immunity. We addressed whether CD200 expression on tumor cells plays a role in immune evasion, thereby preventing elimination of tumor cells by the immune system in a xenograft hu/SCID mouse model, and whether treatment with an antagonistic anti-CD200 antibody affects tumor growth. Methods: The human non-Hodgkins lymphoma cell lines RAJI and Namalwa were transduced with human CD200 and injected subcutaneously together with human peripheral blood lymphocytes (PBL) into NOD/SCID mice. Tumor growth over time was compared among mice that either received CD200-expressing tumor cells or received tumor cells lacking CD200 expression. In subsequent experiments, mice were treated with chimeric or humanized anti-CD200 antibodies (doses ranged from 1 to 20 mg/kg) by intravenous injection. Treatment was either started immediately or 7 days after tumor cell injection. Results: As expected, PBLs reduced CD200-negative RAJI or Namalwa tumor growth by up to 75%. In contrast, growth of RAJI or Namalwa tumors expressing CD200 at levels comparable to that of CLL was not reduced by PBLs. Administration of anti-CD200 antibodies at 5 mg/kg resulted in nearly complete tumor growth inhibition (1/10 mice developed a small tumor) over the course of the study even when treatment was started 7 days after tumor cell injection. Conclusions: CD200 expression on tumor cells inhibits the ability of human lymphocytes to eradicate tumor cells. Treatment of CD200-expressing tumors with antagonistic anti-CD200 antibodies inhibits tumor growth, indicating the potential for anti-CD200 therapy as a promising approach for CLL. No significant financial relationships to disclose.

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Lipińska-Opałka, Agnieszka, Agata Tomaszewska, Jacek Z. Kubiak et Bolesław Kalicki. « Vitamin D and Immunological Patterns of Allergic Diseases in Children ». Nutrients 13, n^o 1 (8 janvier 2021) : 177. http://dx.doi.org/10.3390/nu13010177.

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Vitamin D, in addition to its superior role as a factor regulating calcium-phosphate metabolism, shows wide effects in other processes in the human body, including key functions of the immune system. This is due to the presence of vitamin D receptors in most cells of the human body. In our study, we aimed to assess whether there is a correlation between vitamin D content and the clinical course of allergic diseases as well as establish their immunological parameters in children. We found that vitamin D deficiency was significantly more frequent in the group of children with an allergic disease than in the control group (p = 0.007). Statistically significant higher vitamin D concentrations in blood were observed in the group of children with a mild course of the disease compared to children with a severe clinical course (p = 0.03). In the group of children with vitamin D deficiency, statistically significant lower percentages of NKT lymphocytes and T-regulatory lymphocytes were detected compared to the group of children without deficiency (respectively, p = 0.02 and p = 0.05), which highlights a potential weakness of the immune system in these patients. Furthermore, statistically higher levels of interleukin-22 were observed in the group of children with vitamin D deficiency (p = 0.01), suggesting a proinflammatory alert state. In conclusion, these results confirm the positive relationship between the optimal content of vitamin D and the lesser severity of allergic diseases in children, establishing weak points in the immune system caused by vitamin D deficiency in children.

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Lipińska-Opałka, Agnieszka, Agata Tomaszewska, Jacek Z. Kubiak et Bolesław Kalicki. « Vitamin D and Immunological Patterns of Allergic Diseases in Children ». Nutrients 13, n^o 1 (8 janvier 2021) : 177. http://dx.doi.org/10.3390/nu13010177.

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Vitamin D, in addition to its superior role as a factor regulating calcium-phosphate metabolism, shows wide effects in other processes in the human body, including key functions of the immune system. This is due to the presence of vitamin D receptors in most cells of the human body. In our study, we aimed to assess whether there is a correlation between vitamin D content and the clinical course of allergic diseases as well as establish their immunological parameters in children. We found that vitamin D deficiency was significantly more frequent in the group of children with an allergic disease than in the control group (p = 0.007). Statistically significant higher vitamin D concentrations in blood were observed in the group of children with a mild course of the disease compared to children with a severe clinical course (p = 0.03). In the group of children with vitamin D deficiency, statistically significant lower percentages of NKT lymphocytes and T-regulatory lymphocytes were detected compared to the group of children without deficiency (respectively, p = 0.02 and p = 0.05), which highlights a potential weakness of the immune system in these patients. Furthermore, statistically higher levels of interleukin-22 were observed in the group of children with vitamin D deficiency (p = 0.01), suggesting a proinflammatory alert state. In conclusion, these results confirm the positive relationship between the optimal content of vitamin D and the lesser severity of allergic diseases in children, establishing weak points in the immune system caused by vitamin D deficiency in children.

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Fortin, Jean-François, Benoit Barbeau, Gilles A. Robichaud et Michel J. Tremblay. « T Cell Activation and Regulation of HIV-1 : Same Effectors with Distinct Outcomes ». Canadian Journal of Infectious Diseases 10, suppl c (1999) : 25C—32C. http://dx.doi.org/10.1155/1999/717641.

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The molecular mechanisms that regulate the function of the immune system and human immunodeficiency virus type-1 (HIV-1) gene expression are diverse and complicated. However, replication of HIV-1 is controlled by many of the same regulatory signals that play a crucial role in the transcriptional regulation of the immune system. For example, the viral promoter, as is the case for the immune system, is subject to complex regulation by combinations of cellular transcription factors that may quantitatively and/or qualitatively differ depending on cell types (eg, macrophages versus T lymphocytes) and cell states (eg, undifferentiated versus differentiated or quiescent versus activated). The present review discusses the regulation of HIV-1 gene expression by nuclear factor-kappa Band nuclear factor of activated T cells, and proposes that selective interference of these two cellular transcription factors may be a route to abrogate virus replication without disrupting normal cellular functions. A better understanding of the regulation of HIV-1 gene expression is of utmost importance for the design of molecular approaches that will effectively abrogate virus replication and, ultimately, disease progression.

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Uchida, Takuro, Nobuhiko Hiraga, Michio Imamura, Masataka Tsuge, Hiromi Abe, C. Nelson Hayes, Hiroshi Aikata et al. « Human Cytotoxic T Lymphocyte-Mediated Acute Liver Failure and Rescue by Immunoglobulin in Human Hepatocyte Transplant TK-NOG Mice ». Journal of Virology 89, n^o 19 (5 août 2015) : 10087–96. http://dx.doi.org/10.1128/jvi.01126-15.

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ABSTRACTHepatitis B virus (HBV)-specific cytotoxic T lymphocytes (CTLs) are critical in eliminating infection. We developed an animal model in which HBV-infected human hepatocytes are targeted by HBV-specific CTLs. After HBV inoculation in human hepatocyte-transplanted herpes simplex virus type-1 thymidine kinase-NOG mice, human peripheral blood mononuclear cells (PBMCs) were administered, and albumin, HBV DNA, alanine aminotransferase (ALT), and cytokine levels were analyzed. Histopathological and flow-cytometric analysis of infiltrating human immune cells were performed, and the efficacy of CTL-associated antigen-4 immunoglobulin (CTLA4Ig) against liver damage was evaluated. PBMC treatment resulted in massive hepatocyte damage with elevation of ALT, granzyme A, and gamma interferon and decrease in albumin and HBV DNA. The number of liver-infiltrating human lymphocytes and CD8-positive cells was significantly higher in HBV-infected mice. HBV-specific CTLs were detected by core and polymerase peptide-major histocompatibility complex-tetramer, and the population of regulatory T cells was significantly decreased in HBV-infected mice. Serum hepatitis B surface (HBs) antigen became negative, and HBs antibody appeared. CTLA4Ig treatment strongly inhibited infiltration of mononuclear cells. CTLA4Ig treatment will be used to treat patients who develop severe acute hepatitis B to prevent liver transplantation or lethality. This animal model is useful for virological and immunological analysis of HBV infection and to develop new therapies for severe acute hepatitis B.IMPORTANCEWithout liver transplantation, some HBV-infected patients will die from severe liver damage due to acute overreaction of the immune system. No effective treatment exists, due in part to the lack of a suitable animal model. An animal model is necessary to investigate the mechanism of hepatitis and to develop therapeutic strategies to prevent acute liver failure in HBV infection. We developed an animal model in which HBV-infected human hepatocytes are targeted by human HBV-specific CTLs. In this model, HBV-infected human hepatocytes were transplanted into severely immunodeficient NOG mice in order to reconstruct elements of the human immune system. Using this model, we found that CTL-associated antigen-4 immunoglobulin was able to suppress damage to HBV-infected hepatocytes, suggesting an approach to treatment. This animal model is useful for virological and immunological analysis of HBV infection and to develop new therapies for severe acute hepatitis B.

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Fanzo, Jessica C., Chuan-Min Hu, So Young Jang et Alessandra B. Pernis. « Regulation of Lymphocyte Apoptosis by Interferon Regulatory Factor 4 (IRF-4) ». Journal of Experimental Medicine 197, n^o 3 (3 février 2003) : 303–14. http://dx.doi.org/10.1084/jem.20020717.

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To ensure that homeostasis of the immune system is maintained, the sensitivity of lymphocytes to Fas-mediated apoptosis is differentially regulated during their activation. The molecular mechanisms that link the activation program of lymphocytes to changes in sensitivity to Fas-mediated apoptosis have, however, not been fully characterized. In these studies, we have investigated whether Fas-mediated apoptosis can be regulated by interferon regulatory factor 4 (IRF-4), a lymphoid-restricted member of the IRF family of transcription factors. IRF-4 expression is upregulated during lymphocyte activation and IRF-4–deficient mice have defects in both lymphocyte activation and homeostasis. Here, we show that stable expression of IRF-4 in a human lymphoid cell line that normally lacks IRF-4 leads to a significantly enhanced apoptotic response on Fas receptor engagement. A systematic examination of the downstream effectors of Fas signaling in IRF-4–transfected cells demonstrates an increased activation of caspase-8, as well as an increase in Fas receptor polarization. We demonstrate that IRF-4–deficient mice display defects in activation-induced cell death, as well as superantigen-induced deletion, and that these defects are accompanied by impairments in Fas receptor polarization. These data suggest that IRF-4, by modulating the efficiency of the Fas-mediated death signal, is a novel participant in the regulation of lymphoid cell apoptosis.

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Marquitz, Aron R., Anuja Mathur, Rachel Hood Edwards et Nancy Raab-Traub. « Host Gene Expression Is Regulated by Two Types of Noncoding RNAs Transcribed from the Epstein-Barr Virus BamHI A Rightward Transcript Region ». Journal of Virology 89, n^o 22 (26 août 2015) : 11256–68. http://dx.doi.org/10.1128/jvi.01492-15.

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ABSTRACTIn Epstein-Barr virus-infected epithelial cancers, the alternatively spliced BamHI A rightward transcripts (BARTs) are the most abundant viral polyadenylated RNA. The BART introns form the template for the production of 44 microRNAs (miRNAs), and the spliced and polyadenylated exons form nuclear non-protein-coding RNAs. Analysis of host cell transcription by RNA-seq during latency in AGS cells identified a large number of reproducibly changed genes. Genes that were downregulated were enriched for BART miRNA targets. Bioinformatics analysis predicted activation of the myc pathway and downregulation of XBP1 as likely mediators of the host transcriptional changes. Effects on XBP1 activity were not detected in these cells; however, myc activation was confirmed through use of a myc-responsive luciferase reporter. To identify potential regulatory properties of the spliced, polyadenylated BART RNAs, a full-length cDNA clone of one of the BART isoforms was obtained and expressed in the Epstein-Barr virus (EBV)-negative AGS cells. The BART cDNA transcript remained primarily nuclear yet induced considerable and consistent changes in cellular transcription, as profiled by RNA-seq. These transcriptional changes significantly overlapped the transcriptional changes induced during latent EBV infection of these same cells, where the BARTs are exclusively nuclear and do not encode proteins. These data suggest that the nuclear BART RNAs are functional long noncoding RNAs (lncRNAs). The abundant expression of multiple forms of noncoding RNAs that contribute to growth regulation without expression of immunogenic proteins would be an important mechanism for viral oncogenesis in the presence of a functional immune system.IMPORTANCEInfection with Epstein-Barr virus (EBV) is nearly ubiquitous in the human population; however, it does contribute to the formation of multiple types of cancer. In immunocompromised patients, EBV causes multiple types of lymphomas by expressing viral oncogenes that promote growth and survival of infected B lymphocytes. EBV-positive gastric carcinoma does not require immune suppression, and the viral oncoproteins that are frequent targets for an immunological response are not expressed. This study demonstrates using transcriptional analysis that the expression of various classes of viral non-protein-coding RNAs likely contribute to the considerable changes in the host transcriptional profile in the AGS gastric cancer cell line. This is the first report to show that the highly expressed polyadenylated BamHI A rightward transcripts (BART) viral transcript in gastric carcinoma is in fact a functional viral long noncoding RNA. These studies provide new insight into how EBV can promote transformation in the absence of viral protein expression.

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Voelkl, Simon, Regina AM Gary et Andreas Mackensen. « Suppression of Allogeneic Immune Responses by Human TCRαβ+ CD4− CD8− Double-Negative T Cells. » Blood 112, n^o 11 (16 novembre 2008) : 1536. http://dx.doi.org/10.1182/blood.v112.11.1536.1536.

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Abstract Regulatory T lymphocytes play an important role in the maintenance of immune tolerance to self antigens and are involved in downregulating immune responses in autoimmunity, transplant rejection and tumor immunity. Numerous studies have demonstrated the existence of distinct T cell subsets with immunoregulatory properties. Recently, a novel subset of TCRαβ+ CD4− CD8− (double-negative, DN) T cells has been characterized to specifically suppress immune responses in both mice and humans. Here we demonstrate for the first time that human DN T cells are highly potent suppressor cells of allogeneic CD4+ or CD8+ T cell responses after priming with allogeneic antigen presenting cells (APC). A prerequisite for the immunosuppressive activity is the repetitive priming with allogeneic dendritic cells whereas stimulation with artificial APCs has no effect. Using a transwell system we could show that the suppressive activity against allogeneic immune responses, mediated by DN T cells, requires cell contact. In contrast to murine DN T cells, which eliminate effector T cells via a fas/fasL or perforin/granzyme pathway, human DN T cells suppress the proliferation of alloreactive T cells in an active manner. Taken together, our data indicate that human DN T cells possess strong immunosuppressive effects on alloreactive CD4+ or CD8+ T cells. DN T cells may serve to limit clonal expansion of alloantigen-specific T cells after allogeneic peripheral stem cell transplantation.

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Javed, Asad, et Mohammed Milhem. « Role of Natural Killer Cells in Uveal Melanoma ». Cancers 12, n^o 12 (9 décembre 2020) : 3694. http://dx.doi.org/10.3390/cancers12123694.

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Uveal melanoma has a high mortality rate following metastasis to the liver. Despite advances in systemic immune therapy, treatment of metastatic uveal melanoma (MUM) has failed to achieve long term durable responses. Barriers to success with immune therapy include the immune regulatory nature of uveal melanoma as well as the immune tolerant environment of the liver. To adequately harness the anti-tumor potential of the immune system, non-T cell-based approaches need to be explored. Natural Killer (NK) cells possess potent ability to target tumor cells via innate and adaptive responses. In this review, we discuss evidence that highlights the role of NK cell surveillance and targeting of uveal melanoma. We also discuss the repertoire of intra-hepatic NK cells. The human liver has a vast and diverse lymphoid population and NK cells comprise 50% of the hepatic lymphocytes. Hepatic NK cells share a common niche with uveal melanoma micro-metastasis within the liver sinusoids. It is, therefore, crucial to understand and investigate the role of intra-hepatic NK cells in the control or progression of MUM.

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Semprini, Sabrina, Anne V. McNamara, Raheela Awais, Karen Featherstone, Claire V. Harper, Judith R. McNeilly, Amanda Patist et al. « Peritonitis Activates Transcription of the Human Prolactin Locus in Myeloid Cells in a Humanized Transgenic Rat Model ». Endocrinology 153, n^o 6 (11 avril 2012) : 2724–34. http://dx.doi.org/10.1210/en.2011-1926.

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Prolactin (PRL) is mainly expressed in the pituitary in rodents, whereas in humans, expression is observed in many extrapituitary sites, including lymphocytes. Due to the lack of adequate experimental models, the function of locally produced PRL in the immune system is largely unknown. Using transgenic rats that express luciferase under the control of extensive human PRL regulatory regions, we characterized immune cell responses to thioglycollate (TG)-induced peritonitis. Resident populations of myeloid cells in the peritoneal cavity of untreated rats expressed barely detectable levels of luciferase. In contrast, during TG-induced peritonitis, cell-specific expression in both neutrophils and monocytes/macrophages in peritoneal exudates increased dramatically. Elevated luciferase expression was also detectable in peripheral blood and bone marrow CD11b+ cells. Ex vivo stimulation of primary myeloid cells showed activation of the human extrapituitary promoter by TNF-α, lipopolysaccharide, or TG. These findings were confirmed in human peripheral blood monocytes, showing that the transgenic rat provided a faithful model for the human gene. Thus, the resolution of an inflammatory response is associated with dramatic activation of the PRL gene promoter in the myeloid lineage.

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Ghiringhelli, François, Cédric Ménard, Magali Terme, Caroline Flament, Julien Taieb, Nathalie Chaput, Pierre E. Puig et al. « CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor–β–dependent manner ». Journal of Experimental Medicine 202, n^o 8 (17 octobre 2005) : 1075–85. http://dx.doi.org/10.1084/jem.20051511.

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Tumor growth promotes the expansion of CD4+CD25+ regulatory T (T reg) cells that counteract T cell–mediated immune responses. An inverse correlation between natural killer (NK) cell activation and T reg cell expansion in tumor-bearing patients, shown here, prompted us to address the role of T reg cells in controlling innate antitumor immunity. Our experiments indicate that human T reg cells expressed membrane-bound transforming growth factor (TGF)–β, which directly inhibited NK cell effector functions and down-regulated NKG2D receptors on the NK cell surface. Adoptive transfer of wild-type T reg cells but not TGF-β−/− T reg cells into nude mice suppressed NK cell–mediated cytotoxicity, reduced NKG2D receptor expression, and accelerated the growth of tumors that are normally controlled by NK cells. Conversely, the depletion of mouse T reg cells exacerbated NK cell proliferation and cytotoxicity in vivo. Human NK cell–mediated tumor recognition could also be restored by depletion of T reg cells from tumor-infiltrating lymphocytes. These findings support a role for T reg cells in blunting the NK cell arm of the innate immune system.

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Garrone, P., L. Galibert, F. Rousset, S. M. Fu et J. Banchereau. « Regulatory effects of prostaglandin E2 on the growth and differentiation of human B lymphocytes activated through their CD40 antigen. » Journal of Immunology 152, n^o 9 (1 mai 1994) : 4282–90. http://dx.doi.org/10.4049/jimmunol.152.9.4282.

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Abstract We have studied the effects of prostaglandin E2 (PGE2) on the growth and differentiation of human tonsillar B lymphocytes cultured in the CD40 system with or without IL-4 or IL-10. PGE2 (10(-9) to 10(-6) M) enhanced proliferation of B cells activated through their CD40 Ag, but not their Ig secretion. PGE2 further potentiated both IL-4- and IL-10-induced B cell growth as determined by [3H]TdR uptake and cellular enumeration. The IL-10-induced IgM, IgG, and IgA secretion was enhanced twofold to fourfold after addition of PGE2, whereas IL-4-induced IgG and IgE secretion was inhibited. The IgE production was particularly sensitive as an approximately 90% inhibition was obtained for 10(-7) M PGE2. In addition, PGE2 inhibited IgE production by naive surface IgD+ B cells cultured in the CD40 system, suggesting that PGE2 may interact with mechanisms involved in IgE switching. PGE2 displayed similar effects on cytokine-induced proliferation and Ig secretion of B cells activated by anti-CD40 Abs used in a soluble form. Finally, the PGE2 effects were mimicked by agents increasing cAMP, indicating that the PGE2 activities are likely to depend on the activation of the cAMP pathway. Altogether, the present data indicate that PGE2 stimulates human CD40-activated B cell growth, but differently modulates cytokine-induced differentiation. Thus, in microenvironments supporting the development of an immune response, the secretion of PGE2 by competent cells such as macrophages may participate in the regulation of the humoral response.

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Snijdewint, F. G., P. Kaliński, E. A. Wierenga, J. D. Bos et M. L. Kapsenberg. « Prostaglandin E2 differentially modulates cytokine secretion profiles of human T helper lymphocytes. » Journal of Immunology 150, n^o 12 (15 juin 1993) : 5321–29. http://dx.doi.org/10.4049/jimmunol.150.12.5321.

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Abstract PGE2 is a well known immunomodulator that has multiple effects on the immune system. We demonstrate that PGE2 selectively and dose dependently inhibits IL-2 and IFN-gamma production by mitogenically stimulated human PBL and CD4+ TLC, although at low concentrations IL-4 production is not affected and IL-5 production is even up-regulated. In the tested TLC, PGE2 induced a dramatic elevation (up to 85-fold) of the intracellular cAMP levels. The action of PGE2 may, therefore, be associated with elevation of intracellular cAMP levels, affecting IL-4 and IL-5 differentially from IL-2 and IFN-gamma production. To test this hypothesis we investigated cytokine production by TLC in the absence or presence of agents that affect cAMP levels, either directly (2'-O-dibutyrylcAMP) or through activation of adenylate cyclase (forskolin) or by blocking of phosphodiesterase (3-isobutyl-1-methyl-xanthine). Similar to PGE2, forskolin, 2'-O-dibutyrylcAMP, and 3-isobutyl-1-methyl-xanthine induced inhibition of IL-2 production by TLC and up-regulation of IL-5 production. However, in contrast to PGE2, these agents suppressed IL-4 production although IFN-gamma production was only moderately affected. No significant differences were found between intracellular cAMP levels of mitogenically stimulated Th1 cell clones, which predominantly secrete IL-2 and IFN-gamma, and those of Th2 cell clones, which mainly secrete IL-4 and IL-5. Our results indicate that PGE2 selectively modulates cytokine secretion profiles of human T cells and that elevation of cAMP levels has an important, but possibly not exclusive, regulatory role in this phenomenon.

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Kabbani, M. S., T. B. Sergeeva et L. S. Shchegoleva. « Cell-mediated cytotoxicity (phenotypes of cd8 and cd16) in immune response (Review) ». Novye issledovania 66, n^o 2 (2021) : 36–43. http://dx.doi.org/10.46742/2072-8840-2021-66-2-36-43.

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The immune system is a complex human mechanism that performs a wide range of effector functions, as well as powerful and not yet well-understood regulatory processes are involved in its activities. Phagocytosis is one of the oldest defense mechanisms (paleoimmunity). More evolutionarily young is the mechanism of cellular immunity (neoimmunity). T-lymphocytes mature in the thymus and are divided into: T-suppressors, T-killers, T-helpers and differ in function and surface antigens. Domestic and foreign authors indicate that evolutionarily young Ts cells play a large role in regulating the response, both cellular and humoral immunity. In a number of sources, the authors indicate that northerners of different age and socio-professional groups have an increased level of immunosuppression. The literature over the past 30 years has shown that in extreme conditions, an increase in the concentrations of CD8 +, CD16 + cells is necessary in the formation of an adaptive immune response

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Korbecki, Jan, Szymon Grochans, Izabela Gutowska, Katarzyna Barczak et Irena Baranowska-Bosiacka. « CC Chemokines in a Tumor : A Review of Pro-Cancer and Anti-Cancer Properties of Receptors CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10 Ligands ». International Journal of Molecular Sciences 21, n^o 20 (15 octobre 2020) : 7619. http://dx.doi.org/10.3390/ijms21207619.

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CC chemokines (or β-chemokines) are 28 chemotactic cytokines with an N-terminal CC domain that play an important role in immune system cells, such as CD4+ and CD8+ lymphocytes, dendritic cells, eosinophils, macrophages, monocytes, and NK cells, as well in neoplasia. In this review, we discuss human CC motif chemokine ligands: CCL1, CCL3, CCL4, CCL5, CCL18, CCL19, CCL20, CCL21, CCL25, CCL27, and CCL28 (CC motif chemokine receptor CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10 ligands). We present their functioning in human physiology and in neoplasia, including their role in the proliferation, apoptosis resistance, drug resistance, migration, and invasion of cancer cells. We discuss the significance of chemokine receptors in organ-specific metastasis, as well as the influence of each chemokine on the recruitment of various cells to the tumor niche, such as cancer-associated fibroblasts (CAF), Kupffer cells, myeloid-derived suppressor cells (MDSC), osteoclasts, tumor-associated macrophages (TAM), tumor-infiltrating lymphocytes (TIL), and regulatory T cells (Treg). Finally, we show how the effect of the chemokines on vascular endothelial cells and lymphatic endothelial cells leads to angiogenesis and lymphangiogenesis.

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Zhang, Xueyan, Shupeng Shi, Jie Shen, Mingyi Zhao et Qingnan He. « Functional Immunoregulation by Heme Oxygenase 1 in Juvenile Autoimmune Diseases ». Current Gene Therapy 19, n^o 2 (20 août 2019) : 110–16. http://dx.doi.org/10.2174/1566523219666190710092935.

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An autoimmune disease is an inflammatory condition in which the human body’s immune system attacks normal cells, resulting in decreased and abnormal immune function, which eventually leads to tissue damage or organ dysfunction. In the field of medicine, especially in pediatrics, knowledge about autoimmune diseases is still inadequate. Some common juvenile autoimmune diseases such as Henoch–Schonlein purpura, systemic juvenile idiopathic arthritis, mucocutaneous lymph node syndrome, and autoimmune encephalitis cause considerable public concern. Recent studies revealed that heme oxygenase 1 (HO-1), an enzyme that participates in heme degradation, plays a critical role in the pathogenesis and may regulate autoimmunity. Firstly, it may promote the differentiation of T lymphocytes into CD4+CD25+ regulatory T cells and may be associated with changes in the ratios of cytokines (Th1/Th2 and Th17/Treg) as well. Secondly, HO-1 can regulate the immune system through the secretion of proteins such as transforming growth factors and interleukins. Moreover, increasing the expression of HO-1 can improve vascular function by increasing antioxidant levels. Thus, HO-1 may provide a theoretical basis and guidance for therapeutic management of juvenile autoimmune diseases.

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Gibbons, Jennifer, Mark Pelletier et Robert Ernst. « Yersinia pestis LOS stimulation of U937 cells shows different miRNA expression compared to Escherichia coli LPS stimulation (37.32) ». Journal of Immunology 184, n^o 1_Supplement (1 avril 2010) : 37.32. http://dx.doi.org/10.4049/jimmunol.184.supp.37.32.

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Abstract Lipopolysaccharide (LPS)-stimulated activation of Toll-like Receptor 4 (TLR4) initiates downstream effects central to the inflammatory response that are important for host-pathogen interaction. In eukaryotes, microRNAs or miRNAs are small regulatory RNAs with multiple mRNA targets. There are ~1000 miRNAs encoded in the human genome, with the potential to regulate ~30% of the transcripts. The lipid A component of E. coli LPS is hexa-acylated, resulting in a highly proinflamatory response in human cells. Yersinia pestis synthesizes different lipid A structures depending on growth temperature, correlating to host conditions. Purified tetra-acylated lipooligosaccharide (LOS) of Y. pestis grown at 37○C, mimicking human infection, does not stimulate the innate immune system, whereas purified hexa-acylated LOS of Y. pestis grown at 25○C, mimicking flea infection, stimulates the innate immune system via TLR4, similar to E. coli LPS. Our hypothesis was that miRNA expression would be altered when human cells are incubated with purified LOS from Y. pestis grown at 25○C vs. 37○C. Initial studies in U937 cells using SABiosciences’ miRNA whole genome PCR arrays showed fewer miRNA expression changes in both LOS treatments than reported for LPS-stimulation. However, one modulation of interest is the 10-fold upregulation of miR-601 with 37○C LOS, compared to a 2-fold upregulation with 25○C. These data hint at a novel LOS-related mechanism, given recent reports of NFκB repression via miR-601.

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Markovic, Snezana, Andrea Griesmacher, Alireza Karimi et Mathias Müller. « Effects of cytokine mixtures on the expression of adhesion molecules in human umbilical vein endothelial cells in an in vitro model of inflammation ». Jugoslovenska medicinska biohemija 22, n^o 3 (2003) : 201–6. http://dx.doi.org/10.2298/jmh0303201m.

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As an essential early event in the activation of the immune system increased adherence of circulating neutrophils, lymphocytes and monocytes to the microvascular endothelium is observed. This situation is followed by migration of these cells through vessel walls and their accumulation at sites of tissue injury. This process is mediated by specific cell adhesion molecules being crucial to the generation of immune and inflammatory responses. In this report we demonstrate the effects of cytokine stimulation on endothelial adhesion molecules evoked by incubating HUVECs with two specific cytokine combinations both comprising IL-2, IL-6, IFN-gamma and TNF-alpha, which have been selected because they are elevated in the blood during rejection and infection processes. Combination I additionally include IL-8, which is released by activated monocytes and macrophages and is suggested to be an important angiogenic mediator stimulating the proliferation and migration of endothelial cells. On the other hand combination II contains the two anti-inflammatory cytokines IL-4 and IL-10 which are predominantely synthesized by Th2 cells. While IL-4 demonstrates multiple stimulatory and regulatory effects, IL-10 plays a pivotal part in the regulation of immune responses. Both cytokines block the synthesis of cytokines, such as IL-1, TNF-alpha and IL-12, which are of regulatory importance at the beginning of inflammatory processes. These cytokine mixtures are placed in the center of our studies in order to elucidate their influence on the cell surface expression of a number of adhesion molecules on HUVECs, when combined in multi-component incubation cocktails. The application of these cytokine combinations results in comparable effects significantly increasing the mean fluorescence intensity (MFI) of VCAM-1 slightly up-regulating ICAM-1 surface expression accompanied by the induction of E- and P-selectin expression. These adhesion molecules play pivotal parts in the process of leukocyte transmigration. The experiments reveal a strong up-regulation of these cell surface antigens under conditions mimicking inflammation. This is an essential finding stressing the importance of endothelial cells during the activation of the immune system.

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Spiliopoulou, Polyxeni, Maria Gavriatopoulou, Efstathios Kastritis, Meletios Dimopoulos et Gerasimos Terzis. « Exercise-Induced Changes in Tumor Growth via Tumor Immunity ». Sports 9, n^o 4 (30 mars 2021) : 46. http://dx.doi.org/10.3390/sports9040046.

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Immunity in the tumor microenvironment plays a central role in tumor development. Cytotoxic immune cells act against tumors, while tumors manage to trigger immunosuppressive mechanisms for defense. One bout of physical exercise acutely regulates the immune system inducing short-term redistribution of immune cells among body organs. Repeated acute immune cell mobilization with continuing exercise training results in long-term adaptations. These long-term exercise-induced changes in the immune system arise both in healthy and in diseased populations, including cancer patients. Recent preclinical studies indicate that physical exercise may have a positive impact on intra-tumoral immune cell processes, resulting in tumor suppression. This short narrative review describes the effect of physical exercise on tumor growth as detected via changes in tumor immunity. Research evidence shows that exercise may improve tumor-suppressive functions and may reduce tumor-progressive responses and mechanisms of immune cells, controlling tumor development. Specifically, it seems that exercise in rodents triggers shifts in tumor infiltration of macrophages, neutrophils, natural killer cells, cytotoxic and regulatory T lymphocytes, resulting in tumor suppression. These recent promising data suggest that physical exercise could be combined with anticancer immunotherapies, although exercise parameters like intensity, duration, and frequency need to be evaluated in more detail. More research is needed to investigate the effect of exercise in other immune cell subtypes and their possible connection with tumor growth, whilst information from human tumors is also required.

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Mukherji, B., A. Guha, N. G. Chakraborty, M. Sivanandham, A. L. Nashed, J. R. Sporn et M. T. Ergin. « Clonal analysis of cytotoxic and regulatory T cell responses against human melanoma. » Journal of Experimental Medicine 169, n^o 6 (1 juin 1989) : 1961–76. http://dx.doi.org/10.1084/jem.169.6.1961.

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T cell-mediated immune response against autologous melanoma cells was analyzed, at population and clonal levels, in 31 patients with recurrent and/or metastatic disease. Fresh PBL and lymph node lymphocytes (LNL) from melanoma-involved nodes were not cytotoxic against the respective melanoma cells. When activated in in vitro coculture (IVC) against the autologous melanoma cells in the presence of IL-2, a majority of the activated PBL and LNL became cytotoxic against the autologous targets. The activated effector cells were cloned in limiting dilution microcultures, and growing clones were phenotypically defined and were functionally characterized for cytotoxicity and for potential regulatory function. Functional T cell clones were obtained from 15 of 31 cases. Of these, CTL responses exhibiting cytotoxicity restricted against the autologous melanoma were seen in four cases. All four CTL clones were CD3+, CD8+, and CD4-. Three of these four CTL clones were studied extensively. All three of these CTL clones expressed MHC class I-restricted cytotoxicity. mAb anti-CD3 blocked cytotoxicity in two and enhanced cytotoxicity in the other. Neither autologous sera nor autologous nonactivated fresh PBL modulated the cytotoxic functions of the CTL clones at the effector phase. T cell lines exhibiting regulatory function were obtained in 11 cases. The regulatory T cell lines were CD3+, CD4+, and CD8-. In three cases CD4+ clones amplified the cytotoxic response in the PBL in coculture, while in eight other cases the T cell lines downregulated the cytotoxic responses. Such T cell-mediated down-regulations were either restricted to the autologous system, induced by D/DR antigens expressed by the autologous or allogeneic melanoma cells, or induced by stimulus other than D/DR antigens. Taken together, these findings clearly demonstrate the existence of T cell-mediated cytotoxic and regulatory responses against human melanoma.

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Lundy, Steven, Qi Wu, Lisa Le et Yang Mao-Draayer. « Treatment of MS patients with BG-12 results in a decline in circulating memory T and B lymphocytes (HUM1P.317) ». Journal of Immunology 192, n^o 1_Supplement (1 mai 2014) : 52.17. http://dx.doi.org/10.4049/jimmunol.192.supp.52.17.

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Abstract BG-12 (Tecfidera®) is a recently approved oral treatment for multiple sclerosis that has shown remarkable efficacy. The mechanisms by which BG-12 acts on the human immune system are poorly defined. In the current study, we analyzed the effects of BG-12 treatment on subsets of circulating human T and B lymphocytes using multicolor flow cytometry. Patients treated for four months with BG-12 had decreased total numbers of lymphocytes in their blood that did not reach significance, and no changes in their overall percentages of CD4+ T cells, CD8+ T cells, or CD19+ B cells compared to pretreatment levels. Significant differences were observed when subsets of T and B cells were evaluated. BG-12 treatment resulted in a decrease in percentages of circulating CD4+CD45RO+CD45RAneg memory TH cells and CD8+CD45RO+CD45RAneg memory CTL. Treatment with BG-12 also resulted in significant decreases in circulating CD27+CD19+ memory B cells, and a relative increase in the levels of CD24highCD38highCD19+ regulatory B cells. A CD27+CD24lowCD19+ B cell subset was present in the circulation of some MS patients prior to treatment, but returned to the very low levels found in healthy controls following four months of BG-12 treatment. The data suggest that BG-12 has in vivo down regulatory effects on some lymphocyte subsets, particularly memory T and B cells. Ongoing experiments are focused on measuring functional differences in T and B cell cytokine production in BG-12 treated patients.

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Fujiwara, Mai, Radhika Raheja, Lucien P. Garo, Amrendra K. Ajay, Shrishti Saxena, Roopali Gandhi, Howard L. Weiner et Murugaiyan Gopal. « MicroRNA-92a controls the balance between inflammatory and regulatory T cells in CNS autoimmunity ». Journal of Immunology 204, n^o 1_Supplement (1 mai 2020) : 58.8. http://dx.doi.org/10.4049/jimmunol.204.supp.58.8.

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Abstract Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are mediated by dysregulated autoreactive T cell responses in the central nervous system (CNS). This dysregulation consists of an imbalance between inflammatory T helper cells, such as Th17 cells, and Foxp3+ T regulatory cells (Tregs). MicroRNAs (miRNAs), a class of small non-coding RNAs, are known to play a key role in immune function, and to be dysregulated in EAE and MS. However, identifying specific miRNA pathways that directly connect clinical activity with immune mechanisms in CNS autoimmunity has been a challenge. Previous work has identified miR-92a as one of the most significantly elevated miRNAs in the sera of MS patients, which positively correlates with neurological symptoms and brain atrophy. We now report a major functional role for miR-92a in CNS autoimmunity. MiR-92a is increased during EAE, and its loss strikingly attenuates clinical disease. This attenuation is accompanied by reduced Th17 and increased Treg cells in the CNS. Mechanistically, we found that T cell-intrinsic miR-92a inhibits the development and function of Treg cells while promoting those of Th17 cells by targeting Foxo1, a key transcription factor in T helper cell biology. Preclinical administration of miR-92a inhibitor phenocopies miR-92a loss and ameliorates EAE. Analogous to mice, miR-92a is significantly elevated in MS patient T cells, and reciprocally regulates human Treg and Th17 differentiation. These findings suggest miR-92a skews the Treg/Th17 balance to promote CNS autoimmunity, and that miR-92a silencing may be of therapeutic benefit for MS patients.

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