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Labuda, Jasmine C., Oanh H. Pham, Claire E. Depew, Kevin D. Fong, Bokyung Lee, Jordan A. Rixon, and Stephen J. McSorley. "Circulating immunity protects the female reproductive tract from Chlamydia infection." Proceedings of the National Academy of Sciences 118, no. 21 (May 17, 2021): e2104407118. http://dx.doi.org/10.1073/pnas.2104407118.
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Anatomical positioning of memory lymphocytes within barrier tissues accelerates secondary immune responses and is thought to be essential for protection at mucosal surfaces. However, it remains unclear whether resident memory in the female reproductive tract (FRT) is required for Chlamydial immunity. Here, we describe efficient generation of tissue-resident memory CD4 T cells and memory lymphocyte clusters within the FRT after vaginal infection with Chlamydia. Despite robust establishment of localized memory lymphocytes within the FRT, naïve mice surgically joined to immune mice, or mice with only circulating immunity following intranasal immunization, were fully capable of resisting Chlamydia infection via the vaginal route. Blocking the rapid mobilization of circulating memory CD4 T cells to the FRT inhibited this protective response. These data demonstrate that secondary protection in the FRT can occur in the complete absence of tissue-resident immune cells. The ability to confer robust protection to barrier tissues via circulating immune memory provides an unexpected opportunity for vaccine development against infections of the FRT.
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Han, Ji Won, and Seung Kew Yoon. "Tissue-Resident Lymphocytes: Implications in Immunotherapy for Hepatocellular Carcinoma." International Journal of Molecular Sciences 22, no. 1 (December 28, 2020): 232. http://dx.doi.org/10.3390/ijms22010232.
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Hepatocellular carcinoma (HCC) is a hard-to-treat cancer. The recent introduction of immune checkpoint inhibitors (ICIs) provided viable options to treat HCC, but the response rate is currently not sufficient. Thus, a better understanding of ICI-responding cells within tumors is needed to improve outcomes of ICI treatment in HCC. Recently, tissue-resident memory T (TRM) cells were defined as a subset of the memory T cell population; this cell population is actively under investigation to elucidate its role in anti-tumor immunity. In addition, the role of other tissue-resident populations such as tissue resident regulatory T (Treg) cells, mucosal associated invariant T (MAIT) cells, γδ T cells, and invariant natural killer T (iNKT) cells in anti-tumor immunity is also actively being investigated. However, there is no study that summarizes recent studies and discusses future perspectives in terms of tissue resident lymphocytes in HCC. In this review, we summarize key features of tissue-resident lymphocytes and their role in the anti-tumor immunity. Additionally, we review recent studies regarding the characteristics of tissue-resident lymphocytes in HCC and their role in ICI treatment and other immunotherapeutic strategies.
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Wu, Kang, Fei Wang, Guangwu Guo, Yuqing Li, Li-Jun Qiu, and Xuefeng Li. "CD4+ TSCMs in the Bone Marrow Assist in Maturation of Antibodies against Influenza in Mice." Mediators of Inflammation 2019 (January 10, 2019): 1–10. http://dx.doi.org/10.1155/2019/3231696.
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The bone marrow (BM) is not only a reservoir of hematopoietic stem cells but a repository of immunological memory cells. Further characterizing BM-resident memory T cells would be helpful to reveal the complicated relationship between the BM and immunological memory. In this study, we identified CD122high stem cell antigen-1 (Sca-1) high B cell lymphoma 2 (Bcl-2) high CD4+ stem cell-like memory T cells (TSCMs) as a distinct memory T cell subset, which preferentially reside in the BM, where they respond vigorously to blood-borne antigens. Interestingly, the natural CD4+ TSCMs homing to the BM colocalized with VCAM-1+ IL-15+ IL-7+ CXCL-12+ stromal cells. Furthermore, compared to spleen-resident CD4+ TSCMs, BM-resident TSCMs induced the production of high-affinity antibodies against influenza by B lymphocytes more efficiently. Taken together, these observations indicate that the BM provides an appropriate microenvironment for the survival of CD4+ TSCMs, which broadens our knowledge regarding the memory maintenance of antigen-specific CD4+ T lymphocytes.
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Muthuswamy, Ravikumar, AJ Robert McGray, Sebastiano Battaglia, Wenjun He, Anthony Miliotto, Cheryl Eppolito, Junko Matsuzaki, et al. "CXCR6 by increasing retention of memory CD8+ T cells in the ovarian tumor microenvironment promotes immunosurveillance and control of ovarian cancer." Journal for ImmunoTherapy of Cancer 9, no. 10 (October 2021): e003329. http://dx.doi.org/10.1136/jitc-2021-003329.
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PurposeResident memory CD8 T cells, owing to their ability to reside and persist in peripheral tissues, impart adaptive sentinel activity and amplify local immune response, and have beneficial implications for tumor surveillance and control. The current study aimed to clarify the less known chemotactic mechanisms that govern the localization, retention, and residency of memory CD8 T cells in the ovarian tumor microenvironment.Experimental designRNA and protein expressions of chemokine receptors in CD8+ resident memory T cells in human ovarian tumor-infiltrating CD8+ T cells and their association with survival were analyzed. The role of CXCR6 on antitumor T cells was investigated using prophylactic vaccine models in murine ovarian cancer.ResultsChemokine receptor profiling of CD8+CD103+ resident memory tumor-infiltrating lymphocytes in patients with ovarian cancer revealed high expression of CXCR6. Analysis of The Cancer Genome Atlas (TCGA) (ovarian cancer database revealed CXCR6 to be associated with CD103 and increased patient survival. Functional studies in mouse models of ovarian cancer revealed that CXCR6 is a marker of resident, but not circulatory, tumor-specific memory CD8+ T cells. CXCR6-deficient tumor-specific CD8+ T cells showed reduced retention in tumor tissues, leading to diminished resident memory responses and poor control of ovarian cancer.ConclusionsCXCR6, by promoting retention in tumor tissues, serves a critical role in resident memory T cell-mediated immunosurveillance and control of ovarian cancer. Future studies warrant exploiting CXCR6 to promote resident memory responses in cancers.
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Paik, Daniel H., and Donna L. Farber. "Lung tissue resident memory T cells coordinate effector T cell dynamics during the protective recall response to influenza." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 173.7. http://dx.doi.org/10.4049/jimmunol.200.supp.173.7.
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Abstract Influenza remains a serious public health challenge as the current vaccination strategy cannot protect against new strains that emerge every season. Tissue resident memory T cells (TRM) are a non-circulating memory subset that are generated in the lung after influenza infection or intranasal live vaccination, and these lung TRM have been shown to confer broad cross-strain protection. However, the mechanisms by which both CD4+ and CD8+ TRM mediate their protective response are not well defined. We investigated the tissue specific events during an active murine influenza response, including TRM-mediated protection and effector T cell trafficking. To specifically determine the role of TRM, we treated mice with the drug Fingolimod (FTY720), which sequesters circulating lymphocytes into secondary lymphoid organs, enriching the lung for tissue resident memory cells. We found that TRM immediately confer protection, with reduced viral titers evident as early as day 3 after infection. At later time points beginning at days 4–5 post infection, we determined that CD4+ and CD8+ TRM enhance the recruitment of influenza-specific effector T cells into the lung resident niche as well as CD4+ and CD8+ lymphocyte in situ proliferation as measured by BrdU incorporation. Furthermore, total lung RNA sequencing during active infection and FTY720 treatment reveal candidate TRM-associated chemokine pathways for tissue lymphocyte trafficking. These findings indicate that TRM uniquely influence the cellular dynamics of the lung resident niche to mediate cross-strain protection against influenza.
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Goldrath, Ananda. "Transcriptional Control of Memory T Cell Differentiation." Blood 132, Supplement 1 (November 29, 2018): SCI—7—SCI—7. http://dx.doi.org/10.1182/blood-2018-99-109536.
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Abstract Tissue-resident memory CD8+ T cells (TRM) are optimally positioned at common sites of pathogen exposure, where they elicit rapid and robust antiviral immune responses. However, the molecular signals controlling tissue residency and homeostasis of TRM remain unclear. Exploiting a dual-screening platform integrating computational and RNAi in vivo screening approaches, we have identified transcriptional regulators of TRM differentiation. This strategy revealed numerous transcription factors with indispensable roles in TRM differentiation and homeostasis. Further, we show that tumor infiltrating lymphocytes (TIL) share a core TRM transcriptional signature, and that these factors control TIL residency. These results provide novel insight into the biology of T cell residency, which could be leveraged to enhance vaccine efficacy or adoptive therapy treatments against cancer. Disclosures No relevant conflicts of interest to declare.
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Dong, J. "Human bone marrow-resident and blood-circulating memory T lymphocytes." Zeitschrift für Rheumatologie 77, no. 5 (May 25, 2018): 409–11. http://dx.doi.org/10.1007/s00393-018-0485-7.
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Mami-Chouaib, Fathia, Isabelle Tihy, and Stephanie Corgnac. "Resident memory T cells in antitumor immunity and cancer immunotherapy." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 63.06. http://dx.doi.org/10.4049/jimmunol.208.supp.63.06.
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Abstract Tumor-resident memory T (TRM) cells play an important role in cancer diseases. Accumulating evidence indicates that subpopulations of CD3+CD8+ tumor-infiltrating lymphocytes (TIL) are TRM cells, and are emerging as activated tumor-specific T cells. These TRM are characterized by expression of CD103 integrin and identify tumor-reactive cytotoxic T lymphocytes. Human lung tumor CD103+CD8+ TRM co-express CD49a and CD69, and are associated with a favorable prognosis. They also express a panel of T-cell inhibitory receptors, including PD-1, and are able to kill autologous tumor cells upon blockade of PD-1 with neutralizing antibodies. This CD103+CD8+ TRM subset also emerges as a predictive biomarker of response to PD-1 blockade and expands during anti-PD-1 treatment in responder, but not in non-responder patients. It is now widely admitted that expression of CD103 on activated CD8+ T lymphocytes and persistence of TRM in epithelial tissues requires TGF-β. This cytokine is secreted in the tumor microenvironment in its inactive form bound to latency-associated protein, and is activated by αV integrins on tumor cells and immune cells. Using multiplex immunofluorescence staining on cohorts of anti-PD-(L)1-treated lung cancer patients, we recently showed that decreased expression of tumor αV is associated with improved immunotherapy-related-progression-free survival and correlates with an increased density of CD8+CD103+ TIL. Cancer cell αV activates autocrine TGF-β and participates in inducing CD103 on activated CD8+ T cells. Our more recent studies in mouse tumor models and human cancers demonstrate that different CD8+ TRM subsets participate to response different immune checkpoint inhibitors and therapeutic cancer vaccines. Supported by ARC, INCa, Ligue Supported by ARC, INCa, Ligue
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Siracusa, Francesco, Pawel Durek, Mairi A. McGrath, Özen Sercan‐Alp, Anna Rao, Weijie Du, Carla Cendón, et al. "CD69 + memory T lymphocytes of the bone marrow and spleen express the signature transcripts of tissue‐resident memory T lymphocytes." European Journal of Immunology 49, no. 6 (January 30, 2019): 966–68. http://dx.doi.org/10.1002/eji.201847982.
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Bachnak, Louay, Matthew Godwin, and James B. McLachlan. "Assessing how biological sex effects tissue-resident memory T cell responses to influenza infection." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 182.06. http://dx.doi.org/10.4049/jimmunol.208.supp.182.06.
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Abstract The severity and outcome of influenza virus infection are dependent on various host factors including sex. During the 1918 influenza pandemic, males succumbed to viral infections more than females. Following seasonal influenza vaccination, haemagglutination inhibition titers are significantly higher in females than males. Additionally, the Tlr7 gene that recognizes influenza viruses is located on the X chromosome, resulting in higher expression in females. It is not known whether sex influences non-lymphoid tissue residency of lymphocytes during influenza infection. To explore this, we infected male and female mice intratracheally with 20 PFU influenza virus (A/PR8/H1N1). No significant change was noted in weight loss; however, females displayed a higher survival rate and milder clinical disease nine days post-infection. Lungs of female mice contained greater numbers of influenza-specific tissue-resident CD4+ T-cells compared to males. To assess the role of extra-lymphoid tissues in tissue residency in both sexes, we infected male and female lymphotoxin-a knockout (LTa KO) splenectomized mice that resulted in a total lack of all lymphoid tissues. Physiological differences trended the same for both males and females, with no significant weight difference; however, LTa KO females generated more tissue-resident CD4+ T-cells, while males displayed greater numbers of tissue-resident CD8+ T-cells. Overall, females generated a stronger immune response in the absence of lymphoid tissues in response to the virus. Taken together, our data reveal a novel sex-based effect of viral infection on tissue-resident lymphocytes and non-lymphoid tissue immunity. Supported by a grant from the W.M. Keck Foundation
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Mami-Chouaib, Fathia. "Abstract 1343: CD8+ resident memory T (TRM) cells in tumors." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1343. http://dx.doi.org/10.1158/1538-7445.am2022-1343.
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Abstract Tumor-resident memory T (TRM) cells play an important role in cancer diseases. Accumulating evidence indicates that subpopulations of CD3+CD8+ tumor-infiltrating lymphocytes (TIL) are TRM cells, and are emerging as activated tumor-specific T cells. These TRM cells are characterized by expression of CD103 integrin and identify tumor-reactive cytotoxic T lymphocytes (CTL). Human lung tumor CD103+CD8+ TRM cells co-express CD49a and CD69, and are associated with a favorable prognosis. They also express a panel of T-cell inhibitory receptors, including PD-1, and are able to kill autologous tumor cells upon blockade of PD-1 with neutralizing antibodies. This CD103+CD8+ TRM subset also emerges as a predictive biomarker of response to PD-1 blockade and expands during anti-PD-1 treatment in responder, but not in non-responder lung cancer patients. It is now widely admitted that expression of CD103 on activated CD8+ T lymphocytes and persistence of TRM cells in epithelial tissues requires transforming growth factor (TGF)-β. This cytokine is secreted in the tumor microenvironment in its inactive form bound to latency-associated protein (LAP), and is activated by αV integrins on tumor cells and immune cells. Using multiplex immunofluorescence staining on cohorts of anti-PD-(L)1-treated lung cancer patients, we recently showed that decreased expression of tumor αV is associated with improved immunotherapy-related-progression-free survival (PFS) and correlates with an increased density of CD8+CD103+ TIL. Cancer cell αV activates autocrine TGF-β and participates in inducing CD103 on activated CD8+ T cells. Our more recent studies in mouse tumor models and human cancers demonstrate that different CD8+ TRM subsets participate to response different immune checkpoint inhibitors and therapeutic cancer vaccines. Citation Format: Fathia Mami-Chouaib. CD8+ resident memory T (TRM) cells in tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1343.
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Siracusa, Francesco, Mairi A. McGrath, Patrick Maschmeyer, Markus Bardua, Katrin Lehmann, Gitta Heinz, Pawel Durek, et al. "Nonfollicular reactivation of bone marrow resident memory CD4 T cells in immune clusters of the bone marrow." Proceedings of the National Academy of Sciences 115, no. 6 (January 22, 2018): 1334–39. http://dx.doi.org/10.1073/pnas.1715618115.
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The bone marrow maintains memory CD4 T cells, which provide memory to systemic antigens. Here we demonstrate that memory CD4 T cells are reactivated by antigen in the bone marrow. In a secondary immune response, antigen-specific T cells of the bone marrow mobilize and aggregate in immune clusters together with MHC class II-expressing cells, mostly B lymphocytes. They proliferate vigorously and express effector cytokines, but they do not develop into follicular T-helper cells. Neither do the B lymphocytes develop into germinal center B cells in the bone marrow. Within 10 days, the immune clusters disappear again. Within 30 days, the expanded antigen-specific memory CD4 T cells return to memory niches and are maintained again individually as resting cells. Thus, in secondary immune responses in the bone marrow T-cell memory is amplified, while in germinal center reactions of secondary lymphoid organs humoral memory is adapted by affinity maturation.
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Belz, Gabrielle T., Renae Denman, Cyril Seillet, and Nicolas Jacquelot. "Tissue-resident lymphocytes: weaponized sentinels at barrier surfaces." F1000Research 9 (July 9, 2020): 691. http://dx.doi.org/10.12688/f1000research.25234.1.
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Tissue-resident immune cells stably localize in tissues largely independent of the circulatory system. While initial studies have focused on the recognition of CD8+ tissue-resident memory T (CD8 TRM) cells, it is now clear that numerous cell types such as CD4+ T cells, gd T cells, innate lymphoid cells and mucosal-associated invariant T (MAIT) cells form stable populations in tissues. They are enriched at the barrier surfaces and within non-lymphoid compartments. They provide an extensive immune network capable of sensing local perturbations of the body’s homeostasis. This positioning enables immune cells to positively influence immune protection against infection and cancer but paradoxically also augment autoimmunity, allergy and chronic inflammatory diseases. Here, we highlight the recent studies across multiple lymphoid immune cell types that have emerged on this research topic and extend our understanding of this important cellular network. In addition, we highlight the areas that remain gaps in our knowledge of the regulation of these cells and how a deeper understanding may result in new ways to ‘target’ these cells to influence disease outcome and treatments.
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Machado, Heather E., Nina Friesgaard Øbro, Emily Mitchell, Megan Davies, Anthony R. Green, Kourosh Saeb-Parsy, Daniel James Hodson, David Kent, and Peter J. Campbell. "Life History of Normal Human Lymphocytes Revealed By Somatic Mutations." Blood 134, Supplement_1 (November 13, 2019): 1045. http://dx.doi.org/10.1182/blood-2019-128188.
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Introduction: Mature blood cells harbor a mixture of mutations inherited from ancestral hematopoietic stem cells (HSCs) and mutations accumulated after maturation. The landscape of these somatic mutations in normal blood is poorly mapped, with questions as simple as "how many mutations does a memory T cell accumulate throughout life?" remaining unanswered. This gap in our knowledge is particularly relevant for hematopoietic malignancy- while we know that lymphomas derive from lymphocytes of particular stages of differentiation, we do not know if the patterns we see are reflected in their normal counterparts. Results: In order to characterize normal somatic mutation in lymphocytes, we performed single-cell expansion and whole genome sequencing of over 600 T and B lymphocytes and 200 HSC and progenitor cells across 5 individuals (ages 0-85). All lymphocyte subsets show increased mutation burden with respect to HSCs across all classes of variants (Figure 1). Some of this increase can explained by lymphocyte-specific mutational processes, such as the activity of RAG, accounting for at least 20% of observed structural variants. We also find a striking variation in mutation burden within and between lymphocyte subsets. Microenvironment specific mutational processes dominate the observed differences. Examples of this include germinal center ("non-canonical AID") mutations in memory B cells and UV-like mutations in memory T cells (putatively skin resident cells). Naive B and T cells show a lack of variation in discrete mutational patterns relative to their memory counterparts, and have mutational profiles and mutation burdens more similar to that of HSCs. We also observe differences in the mutational patterns between B and T cells that are indicative of the increased divergence of T lymphocytes from the HSC pool. In general, the mutation burden we observe in normal lymphocytes approach those seen in lymphoma. Conclusions: Our work highlights the substantial genetic diversity in normal lymphocytes, with some cells accumulating thousands of mutations on top of those inherited from the HSC compartment. These mutations can be used to describe the life history of each individual lymphocyte including their exposure to specific microenvironments. Our findings shed light on the biology of these cells and will help differentiate between normal and disease processes. Figure 1 Disclosures No relevant conflicts of interest to declare.
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Yu, Sifei, Suihua Lao, Binyan Yang, and Changyou Wu. "Tissue-Resident Memory-Like CD8+ T Cells Exhibit Heterogeneous Characteristics in Tuberculous Pleural Effusion." Journal of Immunology Research 2021 (April 22, 2021): 1–22. http://dx.doi.org/10.1155/2021/6643808.
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Tissue-resident memory T (TRM) cells are well known to play critical roles in peripheral tissues during virus infection and tumor immunology. Our previous studies indicated that CD69+CD4+ and CD69+CD8+ T cells in tuberculous pleural effusion (TPE) were antigen-specific memory T cells. However, the phenotypical and functional characteristics of CD8+ TRM cells in tuberculosis remain unknown. We found that CD103+CD8+ T cells were the predominant subset of CD103+ lymphocytes in TPE; both CD103 and CD69 expressed on memory CD8+ T cells from TPE were significantly increased compared with those from paired peripheral blood. Phenotypically, CD103+CD69+ and CD103+CD69-CD8+ T cells expressed higher levels of CD45RO than CD103-CD69+CD8+ T cells did; CD103+CD69-CD8+ T cells highly expressed CD27, CD127, and CD62L and some chemokine receptors. We further compared the functional differences among the four distinct CD45RO+CD8+ T subsets identified by CD103 and CD69 expression. In consist with our published results, CD69+CD8+ T cells, but not CD103+CD8+, produced high levels of IFN-γ after treatment with BCG in the presence of BFA. Nevertheless, CD103-CD69+ and CD103+CD69+ memory CD8+ T cells expressed higher levels of Granzyme B, while CD103+CD69- memory CD8+ T cells were characterized as a possibly immunosuppressive subset by highly expressing CTLA-4, CD25, and FoxP3. Furthermore, TGF-β extremely increased CD103 expression but not CD69 in vitro. Together, CD103+CD8+ T cells form the predominant subset of CD103+ lymphocytes in TPE; CD103 and CD69 expression defines distinct CD8+ TRM-like subsets exhibiting phenotypical and functional heterogeneity. Our findings provide an important theoretical basis to optimize and evaluate new tuberculosis vaccines.
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Lai, Chester, George Coltart, Andrew Shapanis, Conor Healy, Ahmad Alabdulkareem, Sara Selvendran, Jeffrey Theaker, et al. "CD8+CD103+ tissue-resident memory T cells convey reduced protective immunity in cutaneous squamous cell carcinoma." Journal for ImmunoTherapy of Cancer 9, no. 1 (January 2021): e001807. http://dx.doi.org/10.1136/jitc-2020-001807.
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BackgroundTumor infiltrating lymphocytes play a key role in antitumor responses; however, while several memory T-cell subtypes have been reported in inflammatory and neoplastic conditions, the proportional representation of the different subsets of memory T cells and their functional significance in cancer is unclear. Keratinocyte skin cancer is one of the most common cancers globally, with cutaneous squamous cell cancer (cSCC) among the most frequent malignancies capable of metastasis.MethodsMemory T-cell subsets were delineated in human cSCCs and, for comparison, in non-lesional skin and blood using flow cytometry. Immunohistochemistry was conducted to quantify CD103+ cells in primary human cSCCs which had metastasized (P-M) and primary cSCCs which had not metastasized (P-NM). TIMER2.0 (timer.cistrome.org) was used to analyze TCGA cancer survival data based on ITGAE expression. Immunofluorescence microscopy was performed to determine frequencies of CD8+CD103+ cells in P-M and P-NM cSCCs.ResultsDespite intertumoral heterogeneity, most cSCC T cells were CCR7−/CD45RA− effector/resident memory (TRM) lymphocytes, with naive, CD45RA+/CCR7− effector memory re-expressing CD45RA, CCR7+/L-selectin+ central memory and CCR7+/L-selectin− migratory memory lymphocytes accounting for smaller T-cell subsets. The cSCC CD8+ T-cell population contained a higher proportion of CD69+/CD103+ TRMs than that in non-lesional skin and blood. These cSCC CD69+/CD103+ TRMs exhibited increased IL-10 production, and higher CD39, CTLA-4 and PD-1 expression compared with CD103− TRMs in the tumor. CD103+ cells were more frequent in P-M than P-NM cSCCs. Analysis of TCGA data demonstrated that high expression of ITGAE (encoding CD103) was associated with reduced survival in primary cutaneous melanoma, breast carcinoma, renal cell carcinoma, kidney chromophobe cancer, adrenocortical carcinoma and lower grade glioma. Immunofluorescence microscopy showed that the majority of CD103 was present on CD8+ T cells and that CD8+CD103+ cells were significantly more frequent in P-M than P-NM cSCCs.ConclusionThese results highlight CD8+CD103+ TRMs as an important functional T-cell subset associated with poorer clinical outcome in this cancer.
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Jiang, Fang, Yuhao Jiao, Kun Yang, Mingyi Mao, Mei Yu, Dongyan Cao, and Yang Xiang. "Single-Cell Profiling of the Immune Atlas of Tumor-Infiltrating Lymphocytes in Endometrial Carcinoma." Cancers 14, no. 17 (September 2, 2022): 4311. http://dx.doi.org/10.3390/cancers14174311.
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Endometrial carcinoma (EC) is a gynecological malignancy with a high incidence; however, thorough studies on tumor-infiltrating lymphocyte (TIL) populations in EC are lacking. We aimed to map the immune atlas of TILs in type I EC via single-cell RNA sequencing (scRNA-seq), mass cytometry and flow cytometry analysis. We found that natural killer (NK) cells and CD8+ T lymphocytes were the major components of TILs in EC patients. We first identified three transcriptionally distinct NK cell subsets, which are likely to possess diverse anti-tumor functions. Additionally, CD103+ cells substantially contributed to the CD8+ T cell population. The signature gene expression of CD103+ CD8+ T cells indicated the tissue residency, immunological memory, and exhaustion properties of this cell subset, which were defined as tissue-resident memory T cells (TRM cells). Moreover, based on scRNA-seq and mass cytometry analysis, we first identified the intrinsic heterogeneity of CD103+ CD8+ T cells that were thought to have a distinct cytotoxicity, cell adhesion and exhaustion status functions. Collectively, distinct subsets of NK cells were found and might shed light on future investigations. CD103+ CD8+ T cell population may be an important immunotherapeutic target in EC and targeting this cell population with combined immunosuppressive therapy might improve the efficacy of immunotherapy for EC.
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Li, Pan, Yixi Zhang, Yanping Xu, Hongcui Cao, and Lanjuan Li. "Characteristics of CD8+ and CD4+ Tissue-Resident Memory Lymphocytes in the Gastrointestinal Tract." Advanced Gut & Microbiome Research 2022 (May 18, 2022): 1–12. http://dx.doi.org/10.1155/2022/9157455.
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Tissue-resident memory T cells (TRMs) are plentiful in the memory T cell pool and persist in barrier sites without recirculating. Increasing evidence has shown that some kinds of CD8+ TRMs and CD4+ TRMs are resident in the gastrointestinal tract (GI), playing an important role in the context of microbiota-immune interactions, infections, maintenance of tissue homeostasis, and tumor surveillance. Although sharing some similar phenotypes, functional properties, and transcriptional regulation with other tissue-TRMs, gastrointestinal tract TRMs (GI-TRMs) have unique phenotypic and functional characteristics reshaped by the local microenvironment. In this review, we will summarize current knowledge on the regulation, maintenance, and function of the CD8+ TRMs and CD4+ TRMs in GI, exploring how these cells contribute to local immune defense, tissue homeostasis, and tumor surveillance.
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Oleinik, E. K., A. V. Churov, and V. M. Oleinik. "IMMUNOLOGICAL MEMORY: THE ROLE OF REGULATORY CELLS (TREGS)." Medical Immunology (Russia) 20, no. 5 (November 6, 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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Strbo, Natasa, Laura Padula, Eva Fisher, Wathsala Wijayalath, Noelle B. Patterson, Jun Huang, Harini Ganeshan, et al. "Secreted heat shock protein gp96-Ig vaccine induces malaria specific intrahepatic CD8 T cell responses." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 168.2. http://dx.doi.org/10.4049/jimmunol.204.supp.168.2.
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Abstract A highly-efficacious and durable malaria vaccine is an essential tool for global malaria eradication. One promising strategy to develop such a vaccine is to induce robust CD8+ T cell-mediated protective immunity against malaria liver stage parasites. We developed and tested a novel malaria vaccine platform based on the secreted form of the heat shock protein gp96 immunoglobulin, (gp96-Ig) to induce malaria antigen-specific liver resident memory CD8+ T cells. Gp96-Ig has ideal properties as an antigen carrier and vaccine adjuvant to activate antigen presenting cells (APCs) and effectively chaperone antigens for cross presentation via MHC I to CD8+ T lymphocytes. Our study shows that vaccination of mice and non-human primate (NHP) animal models with HEK-293 cells transfected with gp96-Ig and two well-known Plasmodium falciparum (Pf) vaccine candidate antigens, circumsporozoite protein (CSP) and apical membrane antigen 1 (AMA1), induce liver infiltrating, antigen-specific, cytotoxic memory CD8+ T cell responses. The majority of the CSP and AMA specific intrahepatic CD8+ T cells expressed CD69 and CXCR3, hallmarks of tissue resident memory T cells (TRM). Also, we found an increased frequency of intrahepatic CD8+ T cells secreting IL-2, which is relevant for maintenance of effective memory responses. Our findings are strongly supportive of a novel gp96-Ig-based malaria vaccine as a unique systemic and liver-homing, liver-stage antigen-specific CD8+ cytotoxic T lymphocyte (CTL) vaccine strategy.
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Gavil, Noah Veis, Milcah Scott, Eyob Weyu, Stephen O’flanagan, Sathi Wijeyesinghe, Olivia Smith, and David Masopust. "Chronic antigen in solid tumors drives a distinct program of T cell residence." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 63.05. http://dx.doi.org/10.4049/jimmunol.208.supp.63.05.
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Abstract Resident-memory T cells (TRM) permanently reside in tissues, surveying the local environment for cognate antigen. Surrogate markers (e.g. CD69, CD103) and transcriptional programs from infection models are used as correlates of residency. Across numerous solid tumor types, TRM-like phenotypes have been identified and correlated with improved prognosis and responsiveness to immunotherapy. However, the migration properties of CD8+ tumor infiltrating lymphocytes (TILs) have not been well described. In this study, we employed parabiosis migration assays in a mouse model of breast cancer and demonstrated that both virus-specific bystander and tumor-specific CD8+ TILs can be resident. Canonical markers of TRM, including CD69, failed to discriminate between resident cells and recent migrants. However, the expression of markers associated with chronic T cell stimulation (PD-1, CD39, Tim-3) identified a population of resident, tumor-specific cells. We further observed that after tumor entry, Tcf-1+PD-1lo tumor-specific T cells progressively acquired the expression of inhibitory receptors, such as Tim-3, correlating with the phenotypes that represent tumor retention and residence. Thus, TRM exist within tumors, durable intratumoral residence was not informed by common markers associated with pathogen-specific TRM that have been described in healthy tissue, but tumor-specific T cells become resident upon tumor antigen recognition and the subsequent upregulation of CD39 and Tim-3. N.G. is a student in the Medical Scientist Training Program (MD/PhD) at the University of Minnesota and is currently supported through the National Cancer Institute (1F30CA253992-01) with past support from the Dr. Warren J. Warwick and Henrietta Holm Warwick Fellowship. Research supported by the National Cancer Institute (1R01CA238439-01A1, D.M.).
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Iaccarino, Ingram, Fatme Mourtada, Sarah Reinke, Paurnima Patil, Gero Doose, Gianni Monaco, Steve Hoffmann, Reiner Siebert, and Wolfram Klapper. "LINC00892 Is an lncRNA Induced by T Cell Activation and Expressed by Follicular Lymphoma-Resident T Helper Cells." Non-Coding RNA 8, no. 3 (June 1, 2022): 40. http://dx.doi.org/10.3390/ncrna8030040.
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Successful immunotherapy in both solid tumors and in hematological malignancies relies on the ability of T lymphocytes to infiltrate the cancer tissue and mount an immune response against the tumor. Biomarkers able to discern the amount and the types of T lymphocytes infiltrating a given tumor therefore have high diagnostic and prognostic value. Given that lncRNAs are known to have a highly cell-type-specific expression pattern, we searched for lncRNAs specifically expressed by activated T cells and at the same time in a kind of lymphoma, follicular lymphoma, where the microenvironment is known to play a critical role in the regulation of antitumor immunity. We focused on a non-coding transcript, annotated as LINC00892, which reaches extremely high expression levels following cell activation in Jurkat cells. Interestingly LINC00892 has an expression pattern resembling that of genes involved in T cell memory. Accordingly, LINC00892 is mostly expressed by the effector memory and helper CD4+ T cell sub-types but not by naïve T cells. In situ analyses of LINC00892 expression in normal lymph nodes and in follicular lymphoma biopsies show that its expression is limited to CD4+ PD1hi T cells, with a subcellular localization within the germinal center matching that of follicular helper T cells. Our analysis therefore suggests that the previously uncharacterized lncRNA LINC00892 could be a useful biomarker for the detection of CD4+ memory T cells in both normal and tumor tissues.
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Son, Young Min, and Jie Sun. "Co-Ordination of Mucosal B Cell and CD8 T Cell Memory by Tissue-Resident CD4 Helper T Cells." Cells 10, no. 9 (September 8, 2021): 2355. http://dx.doi.org/10.3390/cells10092355.
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Adaptive cellular immunity plays a major role in clearing microbial invasion of mucosal tissues in mammals. Following the clearance of primary pathogens, memory lymphocytes are established both systemically and locally at pathogen entry sites. Recently, resident memory CD8 T and B cells (TRM and BRM respectively), which are parked mainly in non-lymphoid mucosal tissues, were characterized and demonstrated to be essential for protection against secondary microbial invasion. Here we reviewed the current understanding of the cellular and molecular cues regulating CD8 TRM and BRM development, maintenance and function. We focused particularly on elucidating the role of a novel tissue-resident helper T (TRH) cell population in assisting TRM and BRM responses in the respiratory mucosa following viral infection. Finally, we argue that the promotion of TRH responses by future mucosal vaccines would be key to the development of successful universal influenza or coronavirus vaccines, providing long-lasting immunity against a broad spectrum of viral strains.
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Longworth, Aaron J., Sharmila Mallya, Tatyana Lev, Maren Pein, Isam Adam, Antony Lincy, Pascal Naef, et al. "Multiomic and spatial immunophenotyping reveals a prominent Runx3 +resident T cell population in the healthy human breast." Journal of Immunology 210, no. 1_Supplement (May 1, 2023): 63.12. http://dx.doi.org/10.4049/jimmunol.210.supp.63.12.
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Abstract The role of Runt-domain related transcription factor 3 (Runx3) in the early development of T cells is well established, however recent work has implicated Runx3 as a driver of residency in barrier tissues such as the lung and intestinal epithelium, as well as in the tumor infiltrating lymphocytes of murine and human melanomas. We have identified a subpopulation of resident T cells in the healthy human breast exhibiting constitutive expression of Runx3. Employing single-cell RNA sequencing paired with concurrent sequencing of T cell receptors (TCRseq, 10× Genomics) and oligo-tagged antibodies (Totalseq, BioLegend) specific to canonical markers of memory and effector T cells, we compared the clonality and transcriptome of T lymphocytes isolated from reduction mammoplasty or tumor-patient-derived contralateral mastectomies to those obtained from matched patient peripheral blood. We subsequently utilized highly-multiplexed spatial immunophenotyping through Co-detection by indexing (CODEX, Akoya Biosciences) to infer the role of Runx3 +resident T cells in the healthy human breast based on informatic analysis of the associated cellular neighborhoods. Our analysis finds an abundant population of highly clonal CD8 +Runx3 +cytotoxic T lymphocytes consistently located in the milk-producing lobular and secretory ductal regions of the healthy adult breast, postulating roles in barrier immunity and tissue reconstruction. Furthermore, marked presence of these cells in the contralateral mastectomies of tumor-bearing patients suggests a protective antitumoral role in nonaffected or cleared tissue. Supported by NIH grant R01 (5R01CACA237376-03), T32 (T32-NS121727-01)
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Gavil, Noah Veis, Eyob Weyu, Milcah C. Scott, Olivia Smith, Sathi Wijeyesinghe, and David Masopust. "Tumor-infiltrating CD8+ T cells can be resident, but exhaustion markers rather than CD69 correlate with residence and tumor specificity." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 57.16. http://dx.doi.org/10.4049/jimmunol.206.supp.57.16.
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Abstract Tumor infiltrating lymphocytes (TILs) represent a heterogeneous population of both pathogen-specific bystander and tumor-specific CD8+ T cells. Within select solid tumors, the expression of exhaustion markers PD-1 and CD39 has been used to discriminate between pathogen-specific and tumor-specific cells. Independent studies across numerous types of solid tumors have also shown that CD8+ TILs can exhibit distinct signatures that imply residence, however, the migrational properties of TILs have not been fully elucidated. In this study, we employed parabiosis migration assays in a mouse model of breast cancer and demonstrated that both virus-specific bystander and tumor-specific CD8+ T cells within the tumor microenvironment (TME) can be resident. Canonical markers of resident-memory T cells (TRM), including CD69, failed to discriminate between resident cells and recent migrants. However, the expression of markers associated with T cell dysfunction (PD-1, CD39, Tim-3, Lag-3) identified a population of tumor-specific cells and was tightly correlated with residence within the TME. Thus, TRM exist within tumors, durable intratumoral residence was not well informed by common markers associated with TRM in healthy tissues, and the expression of exhaustion markers correlated with both tumor specificity and durable residence.
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Noble, Alistair, Lydia Durant, Lesley Hoyles, Anne L. Mccartney, Ripple Man, Jonathan Segal, Samuel P. Costello, et al. "Deficient Resident Memory T Cell and CD8 T Cell Response to Commensals in Inflammatory Bowel Disease." Journal of Crohn's and Colitis 14, no. 4 (October 26, 2019): 525–37. http://dx.doi.org/10.1093/ecco-jcc/jjz175.
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Abstract Background and Aims The intestinal microbiota is closely associated with resident memory lymphocytes in mucosal tissue. We sought to understand how acquired cellular and humoral immunity to the microbiota differ in health versus inflammatory bowel disease [IBD]. Methods Resident memory T cells [Trm] in colonic biopsies and local antibody responses to intraepithelial microbes were analysed. Systemic antigen-specific immune T and B cell memory to a panel of commensal microbes was assessed. Results Systemically, healthy blood showed CD4 and occasional CD8 memory T cell responses to selected intestinal bacteria, but few memory B cell responses. In IBD, CD8 memory T cell responses decreased although B cell responses and circulating plasmablasts increased. Possibly secondary to loss of systemic CD8 T cell responses in IBD, dramatically reduced numbers of mucosal CD8+ Trm and γδ T cells were observed. IgA responses to intraepithelial bacteria were increased. Colonic Trm expressed CD39 and CD73 ectonucleotidases, characteristic of regulatory T cells. Cytokines/factors required for Trm differentiation were identified, and in vitro-generated Trm expressed regulatory T cell function via CD39. Cognate interaction between T cells and dendritic cells induced T-bet expression in dendritic cells, a key mechanism in regulating cell-mediated mucosal responses. Conclusions A previously unrecognised imbalance exists between cellular and humoral immunity to the microbiota in IBD, with loss of mucosal T cell-mediated barrier immunity and uncontrolled antibody responses. Regulatory function of Trm may explain their association with intestinal health. Promoting Trm and their interaction with dendritic cells, rather than immunosuppression, may reinforce tissue immunity, improve barrier function, and prevent B cell dysfunction in microbiota-associated disease and IBD aetiology.
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Shoukry, Naglaa H., Arash Grakoui, Michael Houghton, David Y. Chien, John Ghrayeb, Keith A. Reimann, and Christopher M. Walker. "Memory CD8+ T Cells Are Required for Protection from Persistent Hepatitis C Virus Infection." Journal of Experimental Medicine 197, no. 12 (June 16, 2003): 1645–55. http://dx.doi.org/10.1084/jem.20030239.
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Few hepatitis C virus (HCV) infections resolve spontaneously but those that do appear to afford protective immunity. Second infections are usually shorter in duration and are less likely to persist but mechanisms of virus control in immune individuals have not been identified. In this study we investigated whether memory helper and/or cytotoxic T lymphocytes provide protection in chimpanzees serially reinfected with the virus. Clearance of the first infection took 3–4 mo and coincided with the delayed onset of CD4+ and CD8+ T cell responses. High frequencies of memory T cells targeting multiple HCV proteins were stable over 7 yr of follow-up. Animals were infected for a second time to assess the protective role of memory T cells. In contrast to the prolonged course of the first infection, viremia was terminated within 14 d. Control of this second infection was kinetically linked to rapid acquisition of virus-specific cytolytic activity by liver resident CD8+ T cells and expansion of memory CD4+ and CD8+ T cells in blood. The importance of memory CD8+ T cells in control of HCV infection was confirmed by antibody-mediated depletion of this lymphocyte subset before a third infection. Virus replication was prolonged despite the presence of memory CD4+ T helper cells primed by the two prior infections and was not terminated until HCV-specific CD8+ T cells recovered in the liver. These experiments demonstrate an essential role for memory CD8+ T cells in long-term protection from chronic hepatitis C.
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Highton, Andrew J., Madeleine E. Zinser, Lian Ni Lee, Claire L. Hutchings, Catherine De Lara, Chansavath Phetsouphanh, Chris B. Willberg, Claire L. Gordon, Paul Klenerman, and Emanuele Marchi. "Single-cell transcriptome analysis of CD8+ T-cell memory inflation." Wellcome Open Research 4 (May 9, 2019): 78. http://dx.doi.org/10.12688/wellcomeopenres.15115.1.
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Background: Persistent viruses such as murine cytomegalovirus (MCMV) and adenovirus-based vaccines induce strong, sustained CD8+ T-cell responses, described as memory “inflation”. These retain functionality, home to peripheral organs and are associated with a distinct transcriptional program. Methods: To further define the nature of the transcriptional mechanisms underpinning memory inflation at different sites we used single-cell RNA sequencing of tetramer-sorted cells from MCMV-infected mice, analyzing transcriptional networks in virus-specific populations in the spleen and gut intra-epithelial lymphocytes (IEL). Results: We provide a transcriptional map of T-cell memory and define a module of gene expression, which distinguishes memory inflation in spleen from resident memory T-cells (TRM) in the gut. Conclusions: These data indicate that CD8+ T-cell memory in the gut epithelium induced by persistent viruses and vaccines has a distinct quality from both conventional memory and “inflationary” memory which may be relevant to protection against mucosal infections.
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Galindo, Carmen Maria Anadon, Xiaoqing Yu, kay Hanggi, Subir Biswas, Ricardo Chaurio, Gunjan Mandal, Alexandra Martin, et al. "Ovarian cancer immunogenicity is governed by a narrow subset of progenitor tissue-resident memory T-cells." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 63.04. http://dx.doi.org/10.4049/jimmunol.208.supp.63.04.
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Abstract Despite repeated associations between T-cell infiltration and patient outcome, human ovarian cancer remains poorly responsive to immunotherapy. We report that hallmarks of tumor recognition in ovarian cancer-infiltrating T-cells are primarily restricted to tissue-resident memory (TRM) cells. In mouse models we found that TRM T-cells were better than the re-circulating counterpart at controlling tumor growth. Single-cell RNA/TCR/ATAC sequencing of 83,454 CD3+CD8+CD103+CD69+ TRM cells and 24,175 CD3+CD8+CD103− re-circulating TILs showed that progenitor (TCF1low) tissue-resident memory T-cells (TRMstem cells) arise from transitional recirculating T-cells, which depends on antigen affinity/persistence, resulting in oligoclonal, trogocytic, effector lymphocytes. This effector population develops into proliferative lymphocytes that eventually become exhausted TRMs. Immunohistochemistry of 122 high-grade serous ovarian cancer tissues showed that only TRMstem cells, but not re-circulating TCF1+ T-cells, predict ovarian cancer outcome. Therefore, ovarian cancer is indeed an immunogenic disease that depends on ~13% of CD8+ tumor-infiltrating T-cells (~3% of CD8+ clonotypes), which are primed against high-affinity antigens and maintain waves of effector TRM cells. Support for Shared Resources was provided by Cancer Center Support Grant (CCSG) CA076292 to H. Lee Moffitt Cancer Center and by CCSG CA010815 to The Wistar Institute. This study was supported by grants from NIH (R01CA157664, R01CA124515, R01CA178687, R01CA211913 and U01CA232758 to JRCG; R01CA184185 and RO1CA262121 to PCR.)
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Swaims, Alison, Richard Haaland, Tammy Evans-Strickfaden, Lisa Haadad, Anadi Sheth, L. Lupo, Sarah Cordes, et al. "Recirculating HIV-target T lymphocytes at the mucosal surface of the female genital tract are associated with progesterone increases during the menstrual cycle (MUC2P.938)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 65.21. http://dx.doi.org/10.4049/jimmunol.194.supp.65.21.
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Abstract The Female Genital Tract (FGT) provides a means of entry to opportunistic infections, including HIV, yet immune cell populations at this mucosal surface are poorly defined. We initiated a study of 20 healthy women to characterize resident T cell populations in the lower FGT from lavage and patient-matched blood samples. Surprisingly, we report FGT T cells were primarily CCR7hi memory CD4 T cells (P=<0.0001), consistent with a central memory phenotype and known HIV reservoir. FGT CCR7hi T cells exhibited more frequent expression of HIV susceptibility markers CCR5 and CD38 compared to blood (0.6% vs. 13.6%, P=0.0017), yet retained the ability to migrate to CCR7 ligands, suggesting these cells could migrate from the genital tract into afferent lymphatics. Finally, we demonstrate the frequency of FGT CCR7hi target cells increased during the luteal phase of the menstrual cycle (51.7-72.7), and correlated to progesterone from patient-matched blood (r=0.5176, P=0.0024). These data show that a majority of CD4 T cells at the surface of the FGT in humans do not express canonical resident memory T cell markers, but are primarily a central memory T cell phenotype with the ability to traffic across the mucosal epithelium into underlying tissue. Our findings suggest HIV may directly infect recirculating memory CD4 T cells that traffic virus across the FGT mucosal barrier and progesterone changes throughout the menstrual cycle may predict availability of these cells HIV target cells.
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Labuda, Jasmine C., and Stephen J. McSorley. "Circulating Memory is sufficient for protective immunity to secondary infection with Chlamydia." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 190.13. http://dx.doi.org/10.4049/jimmunol.202.supp.190.13.
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Abstract Chlamydia trachomatis is the most prevalent bacterial STI worldwide and yet no vaccine currently exists to protect the public from this reproductive tract pathogen. Recent reports suggest that Tissue Resident Memory (TRM) T cells are essential for vaccine-induced protection against Chlamydia trachomatis in a mouse infection model. TRM T cells have also been implicated in protective immunity to other reproductive tract pathogens, including Herpes Simplex Virus. Here, we examine a requirement for circulating versus resident memory in protection against secondary infection with Chlamydia muridarum (Cm). When FTY720 was used to block memory lymphocyte circulation, protection against secondary infection was unaltered, demonstrating that local resident mechanisms within the female reproductive tract are sufficient for secondary protection. However, parabiosis surgery of memory and naïve mice demonstrated that naïve mice receiving circulating memory were also fully protected from Cm challenge, indicating that TRM are dispensable for protection. Ongoing experiments are examining the protective capacity of both TRM T cells and circulating memory and whether memory lymphocyte cluster (MLC) formation within the reproductive tract is an essential component of naturally acquired or transferred protective memory. Understanding the differential contribution of resident versus circulating memory to protective responses is vital for the development of new vaccines against Chlamydia infection.
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Tanchot, Corinne, and Benedita Rocha. "Peripheral Selection of T Cell Repertoires: The Role of Continuous Thymus Output." Journal of Experimental Medicine 186, no. 7 (October 6, 1997): 1099–106. http://dx.doi.org/10.1084/jem.186.7.1099.
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We investigated the role of continuous thymus output in the shaping of mature T cell repertoires by studying in vivo the survival of a single clone of mature Rag2-deficient T cell receptor (TCR) transgenic cells at different stages of activation in the absence or presence of thymus export. In the absence of thymus export, TCR-transgenic lymphocytes survived indefinitely in the peripheral pools. When new lymphocytes were produced in the thymus and migrated to the periphery, resident memory T cells were maintained in constant numbers, whereas naive and self-reactive T cells were replaced by recent thymus migrants. This T cell renewal ensured both the efficiency of recall responses to antigens as memory T cells persisted independently of thymus output, and the capacity of the immune system to respond to new antigen stimulation as the naive T cell pool was continuously renewed. Our results also indicate that thymus export is required to control the number of self-reactive peripheral T cells that may invade the peripheral pools if thymus output fails.
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Zhang, Qian, Christopher G. Dove, Jyh Liang Hor, Heardley M. Murdock, Dara M. Strauss-Albee, Jordan A. Garcia, Judith N. Mandl, et al. "DOCK8 regulates lymphocyte shape integrity for skin antiviral immunity." Journal of Experimental Medicine 211, no. 13 (November 24, 2014): 2549–66. http://dx.doi.org/10.1084/jem.20141307.
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DOCK8 mutations result in an inherited combined immunodeficiency characterized by increased susceptibility to skin and other infections. We show that when DOCK8-deficient T and NK cells migrate through confined spaces, they develop cell shape and nuclear deformation abnormalities that do not impair chemotaxis but contribute to a distinct form of catastrophic cell death we term cytothripsis. Such defects arise during lymphocyte migration in collagen-dense tissues when DOCK8, through CDC42 and p21-activated kinase (PAK), is unavailable to coordinate cytoskeletal structures. Cytothripsis of DOCK8-deficient cells prevents the generation of long-lived skin-resident memory CD8 T cells, which in turn impairs control of herpesvirus skin infections. Our results establish that DOCK8-regulated shape integrity of lymphocytes prevents cytothripsis and promotes antiviral immunity in the skin.
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Schürch, Christian M., Chiara Caraccio, and Martijn A. Nolte. "Diversity, localization, and (patho)physiology of mature lymphocyte populations in the bone marrow." Blood 137, no. 22 (June 3, 2021): 3015–26. http://dx.doi.org/10.1182/blood.2020007592.
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Abstract The bone marrow (BM) is responsible for generating and maintaining lifelong output of blood and immune cells. In addition to its key hematopoietic function, the BM acts as an important lymphoid organ, hosting a large variety of mature lymphocyte populations, including B cells, T cells, natural killer T cells, and innate lymphoid cells. Many of these cell types are thought to visit the BM only transiently, but for others, like plasma cells and memory T cells, the BM provides supportive niches that promote their long-term survival. Interestingly, accumulating evidence points toward an important role for mature lymphocytes in the regulation of hematopoietic stem cells (HSCs) and hematopoiesis in health and disease. In this review, we describe the diversity, migration, localization, and function of mature lymphocyte populations in murine and human BM, focusing on their role in immunity and hematopoiesis. We also address how various BM lymphocyte subsets contribute to the development of aplastic anemia and immune thrombocytopenia, illustrating the complexity of these BM disorders and the underlying similarities and differences in their disease pathophysiology. Finally, we summarize the interactions between mature lymphocytes and BM resident cells in HSC transplantation and graft-versus-host disease. A better understanding of the mechanisms by which mature lymphocyte populations regulate BM function will likely improve future therapies for patients with benign and malignant hematologic disorders.
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O'Flanagan, Stephen D., Marco Künzli, Milcah Scott, Noah Veis Gavil, Clare F. Quarnstrom, Olivia Smith, Julia Jackson, Vaiva Vezys, and David Masopust. "Defining the abundance, fate, and function of secondary lymphoid organ resident memory T cells." Journal of Immunology 210, no. 1_Supplement (May 1, 2023): 218.23. http://dx.doi.org/10.4049/jimmunol.210.supp.218.23.
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Abstract For sixty years we have understood that lymphocytes recirculate through blood and secondary lymphoid organs (SLO). Recently, it has been observed that SLOs contain resident populations of memory T cells. Here, we show that conventional isolation techniques grossly underestimate the proportion of SLO CD8+ T RM,and resident cells constitute a substantial fraction of regionalized immunity within LNs. We found that SLO T RMare very long-lived in mice and persist for >500 days after a single infection with LCMV Armstrong. Using a variety of infection models, we observed that the location of primary infection biased the density of SLO T RMto specific draining LNs. Moreover, SLO T RMexpressed a phenotypic relationship with T RMin specific upstream nonlymphoid tissues, and remarkably, retained durable expression of regional homing markers. Upon reactivation, mesenteric LN derived SLO T RMpreferentially homed to the small intestine compared to T CM. Thus, T RMcomprise a substantial fraction of LN memory CD8+ T cells, are refractory to isolation, can be remarkably durable, retain tissue-specific homing potential in the event of reactivation, and likely comprise an underappreciated and underestimated contributor to LN immune surveillance and regional anamnestic immune responses. Supported by fellowship from the University of Minnesota - Department of Microbiology and Immunology Dennis W. Watson Fellowship
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Dornieden, Theresa, Arne Sattler, Anna Pascual-Reguant, Annkathrin Helena Ruhm, Lion Gabriel Thiel, Yasmin Samira Bergmann, Linda Marie Laura Thole, et al. "Signatures and Specificity of Tissue-Resident Lymphocytes Identified in Human Renal Peritumor and Tumor Tissue." Journal of the American Society of Nephrology 32, no. 9 (June 1, 2021): 2223–41. http://dx.doi.org/10.1681/asn.2020101528.
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BackgroundTissue-resident memory T (TRM) cells are known to be important for the first line of defense in mucosa-associated tissues. However, the composition, localization, effector function, and specificity of TRM cells in the human kidney and their relevance for renal pathology have not been investigated.MethodsLymphocytes derived from blood, renal peritumor samples, and tumor samples were phenotypically and functionally assessed by applying flow cytometry and highly advanced histology (multi-epitope ligand cartography) methods.ResultsCD69+CD103+CD8+ TRM cells in kidneys display an inflammatory profile reflected by enhanced IL-2, IL-17, and TNFα production, and their frequencies correlate with increasing age and kidney function. We further identified mucosa-associated invariant T and CD56dim and CD56bright natural killer cells likewise expressing CD69 and CD103, the latter significantly enriched in renal tumor tissues. CD8+ TRM cell frequencies were not elevated in kidney tumor tissue, but they coexpressed PD-1 and TOX and produced granzyme B. Tumor-derived CD8+ TRM cells from patients with metastases were functionally impaired. Both CD69+CD103−CD4+ and CD69+CD103−CD8+ TRM cells form distinct clusters in tumor tissues in proximity to antigen-presenting cells. Finally, EBV, CMV, BKV, and influenza antigen-specific CD8+ T cells were enriched in the effector memory T cell population in the kidney.ConclusionsOur data provide an extensive overview of TRM cells’ phenotypes and functions in the human kidney for the first time, pointing toward their potential relevance in kidney transplantation and kidney disease.
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Ayasoufi, Katayoun, Shelby L. Namen, Delaney Wolf, Zachariah Peter Tritz, Emma Goddery, Christian K. Pfaller, Lauren Gulbicki, et al. "Induction of blood brain barrier disruption through reactivation of virus antigen specific brain resident memory T cells." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 182.31. http://dx.doi.org/10.4049/jimmunol.208.supp.182.31.
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Abstract The contribution of antiviral resident memory T cells (TRM) to blood-brain barrier disruption has not been defined despite the implication of this lymphocyte in clinical encephalitis. We therefore evaluated the capacity of TRM cells to induce CNS vascular permeability in mice which resolved Theiler’s murine encephalomyelitis (TMEV) infection. Following TMEV infection of the brain, persistent populations of virus antigen specific resident memory T cells are induced within the brain. This population of resident memory T cells can be further reactivated at 60 dpi through administration of the cognate immunodominant virus peptide antigen, VP2, inducing blood brain barrier disruption in the process. We determined that brain resident memory T cells expand following reactivation with administered VP2 peptide. This reactivation is associated with infiltration of T cells, and inflammatory myeloid cells into the brain. Importantly, using depletion and T cell sequestrating strategies with low dose anti CD8 antibodies and FTY720, we determined that TRM induced blood-brain barrier disruption is independent of peripheral T cells. We conclude that reactivation of brain TRM cells during peptide administration occurs without dependency on peripheral responses, highlighting the importance of this cell type in inducing neuroinflammation and underlying neuropathology.
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Angeles, Christina V., Jichang Han, Jodi Wilkoswki, and Scott Bresler. "Abstract A007: Resident memory T cells express PD-1 in high grade liposarcoma." Clinical Cancer Research 28, no. 18_Supplement (September 15, 2022): A007. http://dx.doi.org/10.1158/1557-3265.sarcomas22-a007.
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Abstract Objective: Memory T cells play crucial roles in anti-tumor immunity. Tumor-associated resident memory T cells (TRM) have been associated with durable immune response and improved patient survival across multiple tumor types. SARC028, a phase II, multicenter trial of pembrolizumab, a programmed death 1 (PD-1) checkpoint inhibitor immunotherapy, showed promising activity in select histologic subtypes of advanced soft tissue sarcoma (STS), including dedifferentiated liposarcoma (DDLPS). However, there was only a 20% overall response rate. Notably, the patients who did respond to immunotherapy had durable responses, supporting our enthusiasm to understand the potential role for TRM in liposarcoma anti-tumor immunity. The characterization of memory T cells in liposarcoma, and whether TRM are present has not been explored. Design: Fresh retroperitoneal liposarcoma specimens from 8 patients: 3 well-differentiated liposarcoma (WDLPS) and 5 DDLPS were collected. Lymphocytes were analyzed by flow cytometry using T-cell (CD45, CD3, CD4, CD8) and phenotypic markers (CD69, CD62L, CD103, CD49a, PD-1, TIM-3). Results: DDLPS had a 4-fold higher overall T-cell infiltration and a 2.5-fold higher CD8+/CD4+ T-cell ratio than WDLPS. DDLPS contained CD8+ T cells with a CD45RA− CCR7− CD69hi CD62Llo phenotype, characteristic of a TRM response, and well as CD69lo effector memory T (TEM) cells. DDLPS had 3-fold more TRM than WDLPS. DDLPS had a much higher level of activated PD-1+ CD69+ CD8+ resident memory T-cell population compared to WDLPS. Additionally, the population of TRM had higher PD-1 expression compared to TEM in both DDLPS and WDLPS. Conclusions: These data suggest that TRM subsets may contribute to the responsiveness to anti-PD1 therapy in patients with DDLPS. Further investigations may lead to the discovery of TRM-targeted T-cell therapies in DDLPS, which currently has limited treatment options. Citation Format: Christina V. Angeles, Jichang Han, Jodi Wilkoswki, Scott Bresler. Resident memory T cells express PD-1 in high grade liposarcoma [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A007.
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Goswami, Meghali, Karolyn Oetjen, Matthew P. Mulé, Sheenu Sheela, Hong Yuen Wong, Qingguo Liu, Katherine R. Calvo, Catherine E. Lai, and Christopher S. Hourigan. "Increased Frequencies of PD-1+ CD8+ Marrow-Infiltrating Lymphocytes Associated with Highly Clonal T-Lymphocyte Expansions in Relapsed and Refractory AML Patients but Not Healthy Adults." Blood 128, no. 22 (December 2, 2016): 1644. http://dx.doi.org/10.1182/blood.v128.22.1644.1644.
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Abstract Immune checkpoint therapy, particularly inhibition of the PD-1 axis, has shown remarkable efficacy in multiple solid tumor types and some hematological malignancies. Clinical results using anti-PD1 immunotherapy in AML have not yet been reported. Immune checkpoint expression levels and magnitude and/or repertoire of tumor-infiltrating lymphocytes have all been proposed as potential predictive biomarkers of response to such targeted immunotherapy. We therefore examined the marrow infiltrating T-lymphocyte compartment of Relapsed/Refractory Acute Myeloid Leukemia (RR-AML) patients undergoing salvage chemotherapy and that of healthy donors (HD) to determine baseline data for PD-1 expression and T-lymphocyte clonality. Nine adult RR-AML patients recruited to the clinical trial NCT02527447 (Myeloid Malignancies Section, NHLBI, NIH) were analyzed. Cryopreserved bone marrow aspirate mononuclear cells (BMMCs) from these patients prior to salvage chemotherapy (Day 0) and HD (n=9) were assessed using two custom ten-color flow cytometry panels. Frequencies of naive (TN), central memory (TCM), effector memory (TEM), terminal effector (TEMRA), stem cell memory (TSCM), and activated T-lymphocyte subsets, and the expression of PD-1, TIM-3, CTLA-4, 4-1BB on CD8+ T-lymphocyte subpopulations were calculated. DNA extracted from bone marrow of 5 of the RR-AML patients and 5 HD was used for sequencing of the CDR3 region of TCRB gene to evaluate TCR repertoire (ImmunoSEQ, Adaptive Biotechnologies). Immunohistochemistry of pre-treatment bone marrow biopsy sections revealed 10-40% CD3+ cells, typically scattered with focal small aggregations. Flow cytometry of marrow aspirate demonstrated more activated CD8+ CD69+ T-lymphocytes in the marrow of RR-AML patients compared with HD (19.8% vs. 9.4%, p=0.031). Significantly more CD8+ TEMRA T-lymphocytes (60.8% vs. 45.2%, p=0.040) and a trend towards fewer CD8+ TEM T-lymphocytes (19.0% vs. 32.1%, p=0.062) were observed in RR-AML versus HD. An increased proportion of total CD8+ T-lymphocytes in RR-AML had PD-1 expression compared to HD (22.0% vs. 9.2%, p=0.008). This pattern held true for every CD8+ sub-population in AML versus HD: TN (14.0% vs. 4.0%, p=0.014); TCM (24.2% vs. 7.3%, p=0.003); TEMRA (19.6% vs. 10.5%, p=0.060) and TEM (37.3% vs. 16.2%, p=0.004) (Figure 1a). There were no significant differences in frequencies of CD8+ T-lymphocyte subsets or PD-1 expression between Day 0 and Day 28 in AML patients (in 4 patients tested). Furthermore, there was negligible PD-1 co-expression with other immune checkpoint markers and no differences in 4-1BB or CTLA4 expression in AML versus HD. However, we noted significantly higher TIM-3 expression on TN and TCM CD8+ T-lymphocytes in AML (6.5% vs. 2.2%, p=0.001, and 4.5% vs. 0.7%, p=0.021, respectively). Sequencing of productive TCRB gene rearrangements revealed significantly higher average marrow T-cell clonality in AML versus HD (0.232 vs. 0.086, respectively, n=5 AML, n=5 HD). When considering the top 10 most frequent clonotypes for each AML patient and HD, frequencies were found to be much higher in AML than HD (Figure 1b), consistent with large clonal T-lymphocyte expansions in the marrow of RR-AML patients. Furthermore, we identified several TCR clones that were found in AML patients but never seen in HD. Sequencing of an additional cohort of 20 newly diagnosed adult AML patients however discovered that only a subset (25%) of those patients had T cell clonal expansions above the upper limit of that seen in HD. AML is already known to be an immunogenic malignancy, as demonstrated by the measurable efficacy of allogeneic transplantation and donor lymphocyte infusion. Our data demonstrate that the bone marrow tumor microenvironment in RR-AML is enriched for PD-1+ CD8+ marrow-infiltrating lymphocytes, and that large clonal expansions of T-lymphocytes can be found in the bone marrow in these patients. This is suggestive that RR-AML patients, for whom cytotoxic chemotherapy is often suboptimal, may benefit from immune checkpoint blockade therapies, particularly PD-1 axis inhibition, to enable improved immunologic control of AML by autologous T-lymphocytes already resident in the tumor microenvironment. Based in part on these data, a clinical trial of anti-PD-1 immunotherapy in combination with a hypomethylating agent for treatment of relapsed and refractory AML patients will open at our institution. Disclosures Hourigan: Sellas Life Sciences Group: Research Funding.
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Kharwadkar, Rakshin P., Benjamin J. Ulrich, Michelle Chu, Yongyao Fu, Abigail Pajulas, and Mark H. Kaplan. "IL-9 regulates type-2 CD4 tissue resident memory cell mediated allergic airway recall responses." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 94.10. http://dx.doi.org/10.4049/jimmunol.206.supp.94.10.
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Abstract Allergic asthma is a chronic inflammatory lung disease with intermittent flares where patients experience symptoms mediated by memory T cells. Allergen-specific CD4+ tissue resistant memory (Trm) cells in peripheral tissues have been reported to facilitate mucosal barrier immunity. However, the precise role of Trm CD4+ T cells in allergic exacerbations is not clearly defined. In this study we identified interleukin-9 (IL-9)-secreting allergen-specific CD4 T cells with a memory phenotype that regulate recall response to Aspergillus fumigatus. Inhibition of circulating T cells by administering FTY720 in the last month of rest, diminished the total CD4 T cells population in the lung, while the IL-9 secreting CD4 tissue resident cells remained stable. Single-cell RNA-seq and ATAC-seq confirmed the presence of multi-cytokine producing IL-9 secreting CD4 Trms in early recall responses to the allergen. Blockade of IL-9 prior to recall challenge phase reduced overall allergic lung inflammation observed through both flow-cytometry and single cell-RNA-seq analysis. IL-9 neutralization reduced cellularity of several populations in the lung including granulocytes and lymphocytes. Moreover, the expression of genes associated with mucus metaplasia including Muc2, Muc5ac, Muc5b, and Bpifb1 were significantly reduced in type-2 alveolar and epithelial cells with anti-IL-9 treatment. These findings demonstrate that IL-9-producing Trms play an important role in mediating allergic memory responses. IL-9 could be a promising therapeutic target specifically in patients showing symptoms of intermittent allergic response.
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Zhu, Ziang, Yang Li, Han-Ying Huang, Chen Shuzhao, Yang Liu, Yang Liang, and Lingling Shu. "FABP4 Suppresses the Progress of Multiple Myeloma through Enhancing Alarming Function of Bone Marrow Resident Memory T Lymphocytes." Blood 142, Supplement 1 (November 28, 2023): 6580. http://dx.doi.org/10.1182/blood-2023-185445.
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Multiple myeloma (MM) is a hematological malignancy which characterized by malignant plasma cells resident in the bone marrow (BM). The BM microenvironment plays critical roles in the invasion, proliferation and migration of myeloma cells. Despite the therapies of MM improved in recent years, this disease is still incurable and requires precise treatment. Resident memory (TRM) cells are a distinct tissue-localized T cell lineage that is crucial for protective immunity in peripheral tissues. Recent studies reveal TRM cells as a vital component of the host immune response to cancer. TRM-like tumor-infiltrating lymphocytes (TILs) can be found in a wide range of human cancers, where they portend improved prognosis. However, the precise role and mechanism of bone marrow TRM cells in MM still remain elusive. In present study we first found that the accumulation of T RM cells (CD8 +CD44 +CD69 +CD62L -) in BM newly diagnosed MM (NDMM) patients was significantly higher than that of relapse recurrent MM (RRMM) ( Figure A), which was further confirmed by the immunohistochemistry (IHC) staining analysis ( Figure B). By using Seahorse XF e analyzer we found a decrease of oxygen consumption rate (OCR) of T RM cells in RRMM comparing to that of NDMM ( Figure C). Since fatty acid metabolism is important in β oxidation, we further investigated the expression of fatty acid binding proteins (FABP4/FABP5) in T RM cells and showed that FABP4 was dominant in T RM cells of NDMM patients ( Figure D). FABP4 +/+ mice and their relative controls FABP4 -/- mice were adopted to further explore the role and mechanism of T RM cells in MM progression. The abundance of genes related fatty acids β oxidation was significantly decreased in FABP4 -/- T RM cells ( Figure E). The tumor cell viability was decreased in myeloma cells co-cultured with FABP4 -/- T RM cells in the presence of bortezomib ( Figure F). Moreover, the expression of cytotoxic cytokines including IFN γ, TNFα and CXCL10 was significantly higher in FABP4 -/- T RM cells ( Figure G). The alarming function of T RM cells was further enhanced via recruiting more effector T (CD8 +CXCR3 +) cells ( Figure H), therefore the apoptosis of tumor cells was elevated in BM of MM patients. In summary, T RM cells are necessary and sufficient for long-lived protection against tumors. T RM cells derived FABP4 exerts anti-tumor immunity through prolonging the survival of T RM cells and enhancing the recruitment of more effector T cells to suppress the tumor progression ( Figure I). This study suggests that T RM cells might serve as a novel therapeutic target in MM and treatment specific targeting FABP4 might shed light on the development of potential therapeutic strategies for treating MM especially relapse patients. Acknowledgement This project is supported by the Sun Yat-sen University Hundred Talents Program (PT19200101), Natural Science Foundation of Guangdong Province (2022A1515010290).
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Chen, I.-Yu, Fang-Yun Lay, Jean-San Chia, Li-Jen Liao, and Yen-Ling Chiu. "Polyfunctional endogenous EBV-specific T cell response in nasopharyngeal carcinoma." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 89.9. http://dx.doi.org/10.4049/jimmunol.204.supp.89.9.
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Abstract Nasopharyngeal carcinoma (NPC) is associated with Epstein-Barr virus (EBV) infection and can be treated by adoptive transfer of EBV-specific T cells. Although EBV-specific T cell immune response has been identified in NPC, the phenotype and functionality of EBV-specific, tissue-resident memory T cells has not been explored. Tumor-infiltrating lymphocytes (TILs) were isolated from newly-diagnosed NPC and two types of EBV-unrelated malignancies; oral squamous cell carcinoma (OSCC) and renal cell carcinoma (RCC) tissue samples. We found that endogenous EBV-specific T cell response can be detected in the all the tissue types, including NPC, OSCC and RCC, but were rare in peripheral blood. In all tissues, EBV-specific T cells in tumor tissues exhibit resident memory phenotype characterized by high CD69 and CD103 expression and also an exhaustion phenotype characterized by high CD39 and PD-1 expression. Unexpectedly, EBV-specific T cell frequency as well as response magnitude were not enhanced in NPC when compared to other tissue types. The lack of an enhanced EBV-specific T cell response magnitude in NPC tissue confirms the concept that enhancement of EBV-specific immunity by adoptive T cell therapy may improve the outcome of NPC.
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Gonzalez, Yolanda, María Teresa Herrera, Esmeralda Juárez, Miguel Angel Salazar-Lezama, Karen Bobadilla, and Martha Torres. "CD161 Expression Defines a Th1/Th17 Polyfunctional Subset of Resident Memory T Lymphocytes in Bronchoalveolar Cells." PLOS ONE 10, no. 4 (April 23, 2015): e0123591. http://dx.doi.org/10.1371/journal.pone.0123591.
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Egelston, Colt, Gayathri Srinivasan, Christian Avalos, Yinghui Huang, Anthony Rosario, Roger Wang, Grecia Jimenez, et al. "CD8+ tissue resident memory T cells are associated with good prognosis in breast cancer patients." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 196.11. http://dx.doi.org/10.4049/jimmunol.198.supp.196.11.
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Abstract CD8+ Tumor Infiltrating Lymphocytes (TILs) have been shown to correlate with patient prognosis in breast cancer. Recently, resident memory T cells (TRM) have been established as a potent functional subset of memory T cells that exist in peripheral tissue without recirculation. We assayed CD8+ T cells from fresh breast tumors to phenotype memory T cells and found them to be almost exclusively made up of effector memory T cells. Further profiling by examining expression of CD103 and CD69 showed that on average 40% of CD8+ TILs are composed of TRM. Functional analysis of these T cells showed robust production of IFNγ and TNFα by these TRMs suggesting that despite existence in the tumor microenvironment TRMs maintain functional potency. To examine if CD8+ TRM have prognostic value in breast cancer patients, we examined a set of primary tumors from ‘good’ and ‘bad’ outcome patients, which we defined as having a relapse in more than 5 years after diagnosis or in less than 3 years after diagnosis respectively. In good outcome patients TRMs represented 60% of CD8+ T cells found in cancer islands, while only 20% of such in bad outcome patients. Similarly, CD8+ TRMs were observed in higher numbers in both the cancer islands and stroma of good outcome patient tumors in comparison to bad outcome patient tumors. This observed significance was greater than that found for CD8+ T cells in general, highlighting the importance of TRM in affecting patient outcome. Finally we showed that TRMs also exist in non-cancerous breast tissue and are found within the mammary ducts associated with epithelial cells perhaps in surveillance of potential pathogens. We suggest that TRMs are a potential vaccine target for preventing recurrence and metastasis in cancer patients.
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McCully, Michelle L., Kristin Ladell, Svetlana Hakobyan, Robert E. Mansel, David A. Price, and Bernhard Moser. "Epidermis instructs skin homing receptor expression in human T cells." Blood 120, no. 23 (November 29, 2012): 4591–98. http://dx.doi.org/10.1182/blood-2012-05-433037.
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Abstract The localization of memory T cells to human skin is essential for long-term immune surveillance and the maintenance of barrier integrity. Although the mechanisms controlling memory T-cell migration to peripheral tissues are poorly understood, the current paradigm includes the localized secretion of “imprinting” signals from tissue-resident dendritic cells in the draining lymph nodes. Here we show that CCR8 expression by newly activated naive T cells is regulated by skin-specific factor(s) derived primarily from epidermal keratinocytes, thereby providing a mechanism for the preferential expression of CCR8 by skin-resident memory T cells. Importantly, no such effects were observed after coculture with primary cells from skin-unrelated epithelia, including mesothelium and small intestine. The keratinocyte-derived CCR8-inducing factor(s) were soluble, and independent of vitamins A and D. Furthermore, the induction of CCR8 under these conditions correlated with an increase in cutaneous lymphocyte-associated antigen expression. Our findings challenge current tissue homing paradigms, especially those involving CCR10, and emphasize the importance of steady-state epidermis rather than tissue-resident dendritic cells in controlling the localization of memory T cells within human skin.
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Cerapio, Juan Pablo, Marion Perrier, Fréderic Pont, Marie Tosolini, Camille Laurent, Stéphane Bertani, and Jean-Jacques Fournie. "Single-Cell RNAseq Profiling of Human γδ T Lymphocytes in Virus-Related Cancers and COVID-19 Disease." Viruses 13, no. 11 (November 3, 2021): 2212. http://dx.doi.org/10.3390/v13112212.
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The detailed characterization of human γδ T lymphocyte differentiation at the single-cell transcriptomic (scRNAseq) level in tumors and patients with coronavirus disease 2019 (COVID-19) requires both a reference differentiation trajectory of γδ T cells and a robust mapping method for additional γδ T lymphocytes. Here, we incepted such a method to characterize thousands of γδ T lymphocytes from (n = 95) patients with cancer or adult and pediatric COVID-19 disease. We found that cancer patients with human papillomavirus-positive head and neck squamous cell carcinoma and Epstein–Barr virus-positive Hodgkin’s lymphoma have γδ tumor-infiltrating T lymphocytes that are more prone to recirculate from the tumor and avoid exhaustion. In COVID-19, both TCRVγ9 and TCRVγnon9 subsets of γδ T lymphocytes relocalize from peripheral blood mononuclear cells (PBMC) to the infected lung tissue, where their advanced differentiation, tissue residency, and exhaustion reflect T cell activation. Although severe COVID-19 disease increases both recruitment and exhaustion of γδ T lymphocytes in infected lung lesions but not blood, the anti-IL6R therapy with Tocilizumab promotes γδ T lymphocyte differentiation in patients with COVID-19. PBMC from pediatric patients with acute COVID-19 disease display similar γδ T cell lymphopenia to that seen in adult patients. However, blood γδ T cells from children with the COVID-19-related multisystem inflammatory syndrome are not lymphodepleted, but they are differentiated as in healthy PBMC. These findings suggest that some virus-induced memory γδ T lymphocytes durably persist in the blood of adults and could subsequently infiltrate and recirculate in tumors.
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Xu, Haoran. "Tissue Microenvironment Reprograms the Circulating Memory T Cell Differentiation and Enhances Vaccine-Elicited Anti-Metastasis Immunity." Journal of Immunology 210, no. 1_Supplement (May 1, 2023): 83.17. http://dx.doi.org/10.4049/jimmunol.210.supp.83.17.
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Abstract During tumor ontogeny and viral infection, heterologous subsets of CD8+ T lymphocytes provide immediate clearance and durable protection. We utilized model antigen (HIV-1-Gag) expressing melanoma cell line and parabiosis model to investigate the role of different components of memory T cells, including circulating memory T cells (T cirm) and tissue-resident memory T cells (T RM), in melanoma lung metastasis protection. We first proved that T RMgenerated by DNA vaccine intramuscular prime followed by influenza-vectored vaccine intranasal boost immunization regime mediated potent and long-lasting anti-lung metastasis immunity, whereas T cirminduced in different vaccination combinations was not capable to provide sufficient protection. To further explain the mechanism behind the potent T RMgenerated by prime-boost immunization, we found that DNA vaccination elicited a large amount of central memory T cells (T CM) in the circulation and was preferentially differentiated into lung T RMafter the intranasal booster immunization. Single-cell RNA sequencing profile illustrated the tissue microenvironment post mucosal immunization reshaped the differentiation of circulating T CMelicited by systemic immunization and enhanced the anti-metastasis T cell immunity. Thus, our research highlighted the importance of T RMin lung metastasis protection and provided insight into the mechanism of lung T RMestablishment in the prime-boost vaccination.
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Herz, Jasmin, and Dorian McGavern. "Memory T cells convert tissue resident myeloid cells into APCs during clearance of a persistent viral infection (166.28)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 166.28. http://dx.doi.org/10.4049/jimmunol.188.supp.166.28.
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Abstract Persistent viral infections are often very difficult to treat in humans. Adoptive immunotherapy is an approach that involves administration of anti-viral T cells and has shown some promise in the clinic. Our laboratory models adoptive immunotherapy by transferring anti-viral memory T cells into mice persistently infected from birth with lymphocytic choriomeningitis virus (LCMV). Here, we demonstrate that memory T cells can completely purge the brain of persistently infected mice without causing immunopathology or blood brain barrier breakdown. Memory T cells accomplish this by inducing a tailored release of chemoattractants that recruit adaptive immune cells, but few pathogenic innate immune cells (e.g. neutrophils and inflammatory monocytes) into the nervous system. Memory T cells also enlist the support of nearly all brain resident myeloid cells (referred to as microglia) by converting them into CD11c-expressing antigen-presenting cells (APCs). Following conversion, CD11c+ microglia release CCL5 and promote interactions with therapeutic memory T cells in the brain parenchyma. Our two photon imaging studies revealed that anti-viral CD8 T cells are more likely than CD4 T cells to decelerate and form stable interactions with brain-resident APCs. We propose that non-cytopathic viral clearance from the brain by therapeutic memory T cells results from tailored chemoattractant production and conversion of resident myeloid cells into CD11c+ APCs.
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Egelston, Colt, and Peter Lee. "Tissue resident memory T cells are found in the primary and metastatic tumors of breast cancer patients (TUM2P.922)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 71.46. http://dx.doi.org/10.4049/jimmunol.192.supp.71.46.
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Abstract Tumor tissues are composed of significant numbers of Tumor Infiltrating Lymphocytes (TILs), which may include CD8+ T cells, CD4+ T cells, and B cells. Of the T cell population, it is known that these cells are often functionally suppressed and defective in their ability to kill and proliferate. However, little is known about how T cells traffic into tumor sites. Furthermore, it is unclear how the various T cell memory subtypes play a role in attempting to eradicate tumor cells. Such knowledge is critical for the development of successful cancer immunotherapies. Here we assayed peripheral blood mononuclear cells (PBMCs), tumor tissue, and sentinel lymph nodes (SLNs) of breast cancer patients to phenotype memory T cells. We found higher proportions of EM cells among CD8 TILs as compared to SLN CD8 T cells. Conversely, the CD4 compartment in both TILs and SLNs was dominated by CM CD4 T cells. Further analysis showed that breast cancer patient CD8+ TILs in primary tumors were made up of a significant population of Tissue Resident Memory cells (TRMs) as identified by CD103 expression and high CD69 expression. We also showed that the CD8+ TILs found in a metastatic brain lesion of a breast cancer patient also contained TRMs. Finally we showed that healthy breast tissue from a patient with no clinical signs of breast cancer also contained CD8+ TRMs.
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La Manna, Marco Pio, Diana Di Liberto, Marianna Lo Pizzo, Leila Mohammadnezhad, Mojtaba Shekarkar Azgomi, Vincenzo Salamone, Valeria Cancila, et al. "The Abundance of Tumor-Infiltrating CD8+ Tissue Resident Memory T Lymphocytes Correlates with Patient Survival in Glioblastoma." Biomedicines 10, no. 10 (October 1, 2022): 2454. http://dx.doi.org/10.3390/biomedicines10102454.
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Glial tumors alone account for 40% of all CNS tumors and present a low survival rate. The tumor microenvironment is a critical regulator of tumor progression and therapeutic effectiveness in glioma. Growing evidence from numerous studies of human solid tumor-infiltrating CD8+ T cells indicates that tissue-resident memory T cells (TRM) represent a substantial subpopulation of tumor-infiltrating lymphocytes (TILs). Although it is reported that some types of cancer patients with high immune infiltration tend to have better outcomes than patients with low immune infiltration, it seems this does not happen in gliomas. This study aimed to characterize TRMs cells in the glioma tumor microenvironment to identify their potential predictive and prognostic role and the possible therapeutic applications. Fluorescence activated cell sorting (FACS) analysis and immunofluorescence staining highlighted a statistically significant increase in CD8+ TRM cells (CD103+ and CD69+ CD8+ T cells) in gliomas compared to control samples (meningioma). In-silico analysis of a dataset of n = 153 stage IV glioma patients confirmed our data. Moreover, the gene expression analysis showed an increase in the expression of TRM-related genes in tumor tissues compared to normal tissues. This analysis also highlighted the positive correlation between genes associated with CD8+ TRM and TILs, indicating that CD8+ TRMs cells are present among the infiltrating T cells. Finally, high expression of Integrin subunit alpha E (ITGAE), the gene coding for the integrin CD103, and high CD8+ TILs abundance were associated with more prolonged survival, whereas high ITGAE expression but low CD8+ TILs abundance were associated with lower survival.