Journal articles on the topic 'T-cell homeostasi'
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1
Huang, Weishan, Junjie Luo, Lu Huang, Fei Huang, and Avery August. "ITK signals tune CD8+ T cell homeostatic proliferation and anti-tumor immunity (LYM4P.747)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 65.4. http://dx.doi.org/10.4049/jimmunol.192.supp.65.4.
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Abstract IL-2 inducible T cell kinase (ITK) is a Tec family non-receptor tyrosine kinase. Loss of ITK perturbs CD8+ T cell homeostasis and leads to spontaneous acquisition of innate memory/effector phenotype. However, Itk-/- naïve CD8+ T cells develop on an OTI Rag-/- background, and we use these cells to show here that ITK tunes lymphopenia-induced proliferation (LIP) and antigen sensitivity during CD8+ T cell homeostatic expansion. Experimental analysis and computational simulations revealed that in a lymphopenic environment, naïve Itk-/- CD8+ T cells exhibit massive and immediate homeostatic expansion, accompanied by significant death and followed by population collapse. The enhanced immediate expansion of Itk-/- cells is CD8+ T cell-intrinsic and is independent of recipient MHCI, but dependent on donor CD8+ T cell-T cell interaction. The lack of ITK resulted in enhanced antigen sensitivity and effector program in homeostatically expanded (HP) CD8+ T cells. These Itk-/- HP CD8+ T cells exhibit robust anti-tumor immunity in an antigen specific manner, independent of CD4+ T cell help. These data suggest that ITK intrinsically regulates TcR tuning of homeostatic cytokines during homeostasis of CD8+ T cells and that targeting ITK may have clinical benefit in cancer therapy by generating superior anti-tumor responses.
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Lucas, Philip J., Seong-Jin Kim, Spencer J. Melby, and Ronald E. Gress. "Disruption of T Cell Homeostasis in Mice Expressing a T Cell–Specific Dominant Negative Transforming Growth Factor β II Receptor." Journal of Experimental Medicine 191, no. 7 (April 3, 2000): 1187–96. http://dx.doi.org/10.1084/jem.191.7.1187.
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The immune system, despite its complexity, is maintained at a relative steady state. Mechanisms involved in maintaining lymphocyte homeostasis are poorly understood; however, recent availability of transgenic (Tg) and knockout mouse models with altered balance of lymphocyte cell populations suggest that cytokines play a major role in maintaining lymphocyte homeostasis. We show here that transforming growth factor (TGF)-β plays a critical role in maintaining CD8+ T cell homeostasis in a Tg mouse model that specifically overexpresses a dominant negative TGF-β II receptor (DNRII) on T cells. DNRII T cell Tg mice develop a CD8+ T cell lymphoproliferative disorder resulting in the massive expansion of the lymphoid organs. These CD8+ T cells are phenotypically “naive” except for the upregulation of the cell surface molecule CD44, a molecule usually associated with memory T cells. Despite their dominance in the peripheral lymphoid organs, CD8+ T cells appear to develop normally in the thymus, suggesting that TGF-β exerts its homeostatic control in the peripheral immune system.
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Jung, Yong Woo, Hyun Gyung Kim, Curtis J. Perry, and Susan M. Kaech. "CCR7 expression alters memory CD8 T-cell homeostasis by regulating occupancy in IL-7– and IL-15–dependent niches." Proceedings of the National Academy of Sciences 113, no. 29 (July 6, 2016): 8278–83. http://dx.doi.org/10.1073/pnas.1602899113.
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C-C receptor 7 (CCR7) is important to allow T cells and dendritic cells to migrate toward CCL19- and CCL21-producing cells in the T-cell zone of the spleen and lymph nodes. The role of this chemokine receptor in regulating the homeostasis of effector and memory T cells during acute viral infection is poorly defined, however. In this study, we show that CCR7 expression alters memory CD8 T-cell homeostasis following lymphocytic choriomeningitis virus infection. Greater numbers of CCR7-deficient memory T cells were formed and maintained compared with CCR7-sufficient memory T cells, especially in the lung and bone marrow. The CCR7-deficient memory T cells also displayed enhanced rates of homeostatic turnover, which may stem from increased exposure to IL-15 as a consequence of reduced exposure to IL-7, because removal of IL-15, but not of IL-7, normalized the numbers of CCR7-sufficient and CCR7-deficient memory CD8 T cells. This result suggests that IL-15 is the predominant cytokine supporting augmentation of the CCR7−/− memory CD8 T-cell pool. Taken together, these data suggest that CCR7 biases memory CD8 T cells toward IL-7–dependent niches over IL-15–dependent niches, which provides insight into the homeostatic regulation of different memory T-cell subsets.
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Ngoi, Soo M., Justine Lopez, and John T. Chang. "The microtubule-associated protein Lis1 regulates T lymphocyte homeostasis and differentiation." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 204.23. http://dx.doi.org/10.4049/jimmunol.196.supp.204.23.
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Abstract The microtubule-associated protein Lissencephaly 1 (Lis1) is a key regulator of cell division during stem cell renewal and differentiation. We examined the role of Lis1 in T lymphocyte homeostasis and fate diversification in response to microbial infection. T cell-specific deletion of Lis1 resulted in depletion of the peripheral CD4+ and CD8+ T lymphocyte pool, owing to a selective loss of homeostatic, cytokine-induced proliferation. By contrast, cognate antigen-triggered proliferation was relatively unaffected in CD8+ T cells, enabling Lis1-deficient T cells to differentiate into terminal effector cells in response to microbial infection. Strikingly, however, Lis1-deficient CD8+ T cells failed to develop into long-lived memory lymphocytes. Taken together, these findings suggest that Lis1 plays an important role in T cell homeostasis and the generation of memory T lymphocytes.
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Haegert, David G. "Multiple Sclerosis: A Disorder of Altered T-Cell Homeostasis." Multiple Sclerosis International 2011 (2011): 1–6. http://dx.doi.org/10.1155/2011/461304.
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Uncertainty exists as to whether similar or different mechanisms contribute to the pathogenesis of different subtypes of multiple sclerosis (MS). Detailed analysis of naive T cell homeostasis shows that patients with relapsing-remitting MS (RRMS) and with primary progressive MS (PPMS) have early-onset thymic involution that causes reduced thymic output. The reduced thymic output leads to secondary peripheral homeostatic alterations in naïve CD4 T-cells, which closely mimic T-cell alterations observed in an experimental animal model of diabetes mellitus. Homeostatic T-cell receptor (TCR) signalling and proliferation of naïve T cells are induced by self-peptides. Consequently, the findings of increased TCR signalling of naïve CD4 T-cells, without increased proliferation, in PPMS, and the increased homeostatic proliferation of naïve CD4 T-cells in RRMS favour the development of autoimmunity. Thus, it seems highly likely that peripheral T-cell alterations secondary to a thymic abnormality contribute to the pathogenesis of both MS subtypes.
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Davila, Micha L., Yaoyao Fu, Jie Yang, and Na Xiong. "Role of CCR10 and CCL27 in skin resident T cell development and homeostasis." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 137.7. http://dx.doi.org/10.4049/jimmunol.196.supp.137.7.
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Abstract The skin hosts numerous immune cell subsets which generate synergistic responses to a variety of stimuli including foreign antigens, pathogens and commensal bacteria. Each stimulus is unique and calls for a specific and balanced response; any disruption of this homeostasis can lead to complications such as inflammatory diseases. T cells in the skin are a key player in the response to infection, maintenance of commensal bacterial, and tissue homeostasis. Thus, elucidating the mechanisms regulating T cell migration, establishment, and maintenance within the skin is a high priority. CCR10, a receptor expressed on the majority of skin resident T cells, has a complex role in the development of skin-resident T cells through interaction with its skin-specific receptor CCL27. Preliminary data from our analysis of T-cell specific phenotypes in CCL27a knockout mice demonstrates a preferential reduction of Treg cells in the skin, highlighting the importance of CCL27a in the establishment of skin resident Treg cells under homeostatic conditions. Furthermore, we found CCR10+ resident CD8+ T cells contribute to the homeostatic maintenance of Treg and CD4+ effector T cells in the skin. Defective establishment of CCR10-knockout CD8+ T cells in the skin was shown to correlate with a reduction of skin-resident Treg cells. Skin-resident CD8+ T cells express high amounts of B7.2, a ligand for CTLA-4 which is highly expressed on Treg cells in the skin. In vitro co-culture of purified skin CD8+ and Treg cells suggests B7-2/receptor interaction is important for CD8+ cell-mediated survival of Treg cells. These findings will greatly aid in further understanding the development and homeostasis of skin resident T cells.
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Lucas, Philip J., Seong-Jin Kim, Crystal L. Mackall, William G. Telford, Yu-Waye Chu, Frances T. Hakim, and Ronald E. Gress. "Dysregulation of IL-15-mediated T-cell homeostasis in TGF-β dominant-negative receptor transgenic mice." Blood 108, no. 8 (October 15, 2006): 2789–95. http://dx.doi.org/10.1182/blood-2006-05-025676.
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AbstractT-cell subpopulations, defined by their expression of CD4, CD8, naive, and memory cell-surface markers, occupy distinct homeostatic compartments that are regulated primarily by cytokines. CD8+ memory T cells, as defined by CD44hi surface expression, are dependent on IL-15 as a positive regulator of their homeostatic maintenance. Manipulation of IL-15 signaling through gene aberration, overexpression, or receptor alterations has been shown to dramatically affect T-cell homeostasis, with overexpression leading to fatal leukemia. Here we show that TGF-β is the critical negative regulator of murine CD8+ memory T-cell homeostasis with direct opposition to the positive effects of IL-15. This negative regulation is mediated, at least in part, by the ability of TGF-β to modulate expression of the β-chain of the IL-15 receptor, thus establishing a central axis between these 2 cytokines for homeostatic control of CD8+ memory T-cell populations. These data establish TGF-β as a critical and dominant tumor-suppressor pathway opposing IL-15-mediated CD8+ T-cell expansion and potential malignant transformation.
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Ikegawa, Shuntaro, Yusuke Meguri, Takumi Kondo, Hiroyuki Sugiura, Yasuhisa Sando, Makoto Nakamura, Miki Iwamoto, Yoshinobu Maeda, and Ken-ichi Matsuoka. "PTCy ameliorates GVHD by restoring regulatory and effector T-cell homeostasis in recipients with PD-1 blockade." Blood Advances 3, no. 23 (December 10, 2019): 4081–94. http://dx.doi.org/10.1182/bloodadvances.2019000134.
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Key Points PD-1 blockade exacerbated GVHD by altering the homeostasis of Tregs and effector T cells after HSCT. PTCy ameliorated GVHD after PD-1 blockade by restoring the homeostatic balance of T-cell subsets.
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Gustafson, Claire Ellen, Simon Lambert, Cornelia M. Weyand, and Jorg J. Goronzy. "Homeostatic maintenance of human T cells in bioengineered secondary lymphoid organoids – a model for studying age-related immune decline." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 154.2. http://dx.doi.org/10.4049/jimmunol.204.supp.154.2.
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Abstract During aging, homeostatic maintenance of naïve T cells in secondary lymphoid tissues (SLT) is lost, leading to reduced cell numbers, a loss of stem-like properties and partial differentiation. The underlying mechanisms that drive these changes are unclear. Moreover, mechanistic studies in humans are currently limited by poor T cell homeostasis in standard in vitro culture and in humanized mice. Thus, we sought to develop a robust culture system mimicking SLT that maintains human T cell survival and homeostasis. In our system, we encapsulate human T cells into a bioengineered matrix containing primary fibroblastic reticular cells (FRC), which are stromal cells that support T cell homeostasis within SLT in vivo. Within these SLT-like organoids, resting naïve T cells from young donors exhibited significantly higher viability and dramatically longer survival times (> 3 weeks) compared with two-dimensional (2D) T cell-FRC cultures. Survival was not driven by T cell receptor activation or proliferation. Moreover, naïve T cells maintained a quiescent-like phenotype (CD45RAhighCD27high), which is a phenotype preferentially lost by naïve T cells in 2D culture as well as during aging. Using small molecule screening, we found that inhibition of adenosine receptor signaling caused naïve T cells to break quiescence and acquire a partially differentiated phenotype (CD45RAlow) similar to that of naïve T cells from older individuals. As old naïve T cells expressed similar levels of adenosine receptors as young, these data suggest that the loss of adenosine within SLT may contribute to immune aging. Thus, we have developed a new, malleable model system that allows for mechanistic investigation into human T cell homeostasis and the effects of aging.
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Afzal, Samia, Zhenyue Hao, Momoe Itsumi, Yasser Abouelkheer, Dirk Brenner, Yunfei Gao, Andrew Wakeham, et al. "Autophagy-independent functions of UVRAG are essential for peripheral naive T-cell homeostasis." Proceedings of the National Academy of Sciences 112, no. 4 (January 12, 2015): 1119–24. http://dx.doi.org/10.1073/pnas.1423588112.
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UV radiation resistance-associated gene (UVRAG) encodes a tumor suppressor with putative roles in autophagy, endocytic trafficking, and DNA damage repair but its in vivo role in T cells is unknown. Because conditional homozygous deletion of Uvrag in mice results in early embryonic lethality, we generated T-cell–specific UVRAG-deficient mice that lacked UVRAG expression specifically in T cells. This loss of UVRAG led to defects in peripheral homeostasis that could not be explained by the increased sensitivity to cell death and impaired proliferation observed for other autophagy-related gene knockout mice. Instead, UVRAG-deficient T-cells exhibited normal mitochondrial clearance and activation-induced autophagy, suggesting that UVRAG has an autophagy-independent role that is critical for peripheral naive T-cell homeostatic proliferation. In vivo, T-cell–specific loss of UVRAG dampened CD8+ T-cell responses to LCMV infection in mice, delayed viral clearance, and impaired memory T-cell generation. Our data provide novel insights into the control of autophagy in T cells and identify UVRAG as a new regulator of naïve peripheral T-cell homeostasis.
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Tan, Joyce T., Bettina Ernst, William C. Kieper, Eric LeRoy, Jonathan Sprent, and Charles D. Surh. "Interleukin (IL)-15 and IL-7 Jointly Regulate Homeostatic Proliferation of Memory Phenotype CD8+ Cells but Are Not Required for Memory Phenotype CD4+ Cells." Journal of Experimental Medicine 195, no. 12 (June 17, 2002): 1523–32. http://dx.doi.org/10.1084/jem.20020066.
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The overall size and composition of the pool of naive and memory T cells are tightly regulated by homeostatic mechanisms. Recent work has shown that homeostasis of naive T cells is controlled by two factors, self-major histocompatibility complex (MHC)/peptide ligands and a cytokine, interleukin (IL)-7. In particular, contact with these two factors is required for naive CD4+ and CD8+ cells to undergo “homeostatic” proliferation, i.e., proliferation induced as a consequence of severe T cell depletion. In contrast to naive T cells, the factors that drive memory T cells to undergo homeostatic proliferation are poorly understood. To address this issue, purified memory phenotype CD4+ and CD8+ cells from normal mice were adoptively transferred into various gene-knockout mice rendered T cell–deficient by sublethal irradiation. Three findings are reported. First, unlike naive T cells, homeostatic proliferation of memory T cells is largely MHC independent. Second, memory CD8+ cells can utilize either IL-7 or IL-15 to undergo homeostatic proliferation; however, in the absence of both IL-7 and IL-15, homeostatic proliferation fails to occur. Third, unlike memory CD8+ cells, homeostatic proliferation of memory CD4+ cells is independent of IL-7 and IL-15 (also IL-4). Thus, the homeostatic proliferation mechanisms that control memory CD8+ cells and memory CD4+ cells are quite distinct.
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Shin, Haina, Shawn D. Blackburn, Joseph N. Blattman, and E. John Wherry. "Viral antigen and extensive division maintain virus-specific CD8 T cells during chronic infection." Journal of Experimental Medicine 204, no. 4 (April 9, 2007): 941–49. http://dx.doi.org/10.1084/jem.20061937.
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Efficient maintenance of memory CD8 T cells is central to long-term protective immunity. IL-7– and IL-15–driven homeostatic proliferation is essential for long-term memory CD8 T cell persistence after acute infections. During chronic infections, however, virus-specific CD8 T cells respond poorly to these cytokines. Yet, virus-specific CD8 T cells often persist for long periods of time during chronic infections. We have addressed this apparent paradox by examining the mechanism for maintaining virus-specific CD8 T cells during chronic infection. We find that homeostatic cytokines (e.g., IL-7/15), inflammatory signals, and priming of recent thymic emigrants are not sufficient to maintain virus-specific CD8 T cells over time during chronic infection. Rather, our results demonstrate that viral peptide is required for virus-specific CD8 T cell persistence during chronic infection. Moreover, this viral antigen-dependent maintenance results in a dramatically different type of T cell division than is normally observed during memory T cell homeostasis. Rather than undergoing slow, steady homeostatic turnover during chronic viral infection, CD8 T cells undergo extensive peptide-dependent division, yet cell numbers remain relatively stable. These results indicate that antigen-specific CD8 T cell responses during persisting infection are maintained by a mechanism distinct from that after acute infection.
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Serwold, Thomas, Eric Vroegindeweij, MiJeong Kim, and Sara Vazquez. "Homeostatic proliferation of thymocytes is controlled through dynamic regulation of delta like 4 (HEM7P.229)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 188.9. http://dx.doi.org/10.4049/jimmunol.194.supp.188.9.
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Abstract The thymus has a remarkable ability to sustain T cell development and T cell output from thymuses with quantitative and qualitative deficiencies in T cell progenitors, suggesting a role for homeostatic pathways in controlling T cell development. However, these homeostatic pathways are currently uncharacterized. We find that Delta-like 4 (Dll4), which is expressed on thymic epithelial cells (TECs) and is essential for driving T cell lineage commitment, is dynamically regulated in response to thymocyte deficiencies, and plays a major role in thymocyte homeostasis. We observe that TECs express elevated Dll4 levels in multiple lines of mice that have defective T cell development, as well as in mice subjected to antibody or irradiation-induced thymocyte depletion. Recovery of thymus cellularity after thymic injury is accompanied by re-establishment of normal levels of Dll4. In vitro proliferation of thymocytes increases proportionally in response to elevated levels of Dll4 expressed on stromal cells. Furthermore, Dll4 levels on stromal cells diminish in response to interactions with thymocytes themselves. These findings implicate dynamic control of Dll4 levels as a major homeostatic mechanism that regulates thymocyte proliferation.
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Yang, Jie, Shaomin Hu, and Na Xiong. "Selective programming of regulatory CCR10+ innate lymphoid cells in skin-draining lymph nodes for skin immune homeostatic regulation (MUC2P.918)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 65.1. http://dx.doi.org/10.4049/jimmunol.194.supp.65.1.
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Abstract Innate lymphoid cells (ILCs) are preferentially localized in barrier tissues where they function in homeostatic regulation but also contribute to inflammatory diseases. Mechanisms regulating establishment of ILCs in barrier tissues with diverse functions in homeostasis and inflammation are poorly understood. We found that microenvironments of lymph nodes (LNs) program ILCs with homing and functional potentials for their tissue-specific functions. In skin- but not mucosal tissue-draining LNs, ILCs were continuously activated to acquire regulatory properties with high expression of CCR10 for their localization into the skin. Upon analyzing Rag1-/-, Foxn1-/-, Foxp3-/- and skin-inflammation-induced mice, we found that the generation of CCR10+ ILCs in skin-draining LNs and their establishment in the skin required T cell-regulated homeostatic environments and were suppressed during inflammation. Reciprocally, CCR10+ ILCs also promote homeostasis of resident T cells. When transferred into IL2Rγ-/-Rag2-/- mice that lack ILCs, CD4+ T cells could not establish homeostasis in the skin, with notably reduced regulatory T cells and increased effector T cells expressing high levels of inflammatory cytokines, demonstrating cross-regulation of CCR10+ ILCs and CD4+ T cells to promote immune homeostasis in the skin. Our studies reveal a process programming tissue-specific ILCs in LNs for their localization and function in local tissues.
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Sprent, Jonathan, Jae‐Ho Cho, Onur Boyman, and Charles D. Surh. "T cell homeostasis." Immunology & Cell Biology 86, no. 4 (March 25, 2008): 312–19. http://dx.doi.org/10.1038/icb.2008.12.
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Almeida, Afonso R. M., José A. M. Borghans, and António A. Freitas. "T Cell Homeostasis." Journal of Experimental Medicine 194, no. 5 (August 27, 2001): 591–600. http://dx.doi.org/10.1084/jem.194.5.591.
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We developed a novel experimental strategy to study T cell regeneration after bone marrow transplantation. We assessed the fraction of competent precursors required to repopulate the thymus and quantified the relationship between the size of the different T cell compartments during T cell maturation in the thymus. The contribution of the thymus to the establishment and maintenance of the peripheral T cell pools was also quantified. We found that the degree of thymus restoration is determined by the availability of competent precursors and that the number of double-positive thymus cells is not under homeostatic control. In contrast, the sizes of the peripheral CD4 and CD8 T cell pools are largely independent of the number of precursors and of the number of thymus cells. Peripheral “homeostatic” proliferation and increased export and/or survival of recent thymus emigrants compensate for reduced T cell production in the thymus. In spite of these reparatory processes, mice with a reduced number of mature T cells in the thymus have an increased probability of peripheral T cell deficiency, mainly in the naive compartment.
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Paiardini, Mirko, Barbara Cervasi, Jessica C. Engram, Shari N. Gordon, Nichole R. Klatt, Alagarraju Muthukumar, James Else, et al. "Bone marrow–based homeostatic proliferation of mature T cells in nonhuman primates: implications for AIDS pathogenesis." Blood 113, no. 3 (January 15, 2009): 612–21. http://dx.doi.org/10.1182/blood-2008-06-159442.
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AbstractBone marrow (BM) is the key hematopoietic organ in mammals and is involved in the homeostatic proliferation of memory CD8+ T cells. Here we expanded on our previous observation that BM is a preferential site for T-cell proliferation in simian immunodeficiency virus (SIV)–infected sooty mangabeys (SMs) that do not progress to AIDS despite high viremia. We found high levels of mature T-cell proliferation, involving both naive and memory cells, in healthy SMs and rhesus macaques (RMs). In addition, we observed in both species that lineage-specific, BM-based T-cell proliferation follows antibody-mediated in vivo CD4+ or CD8+ T-cell depletion, thus indicating a role for the BM in maintaining T-cell homeostasis under depleting circumstances. We also observed that, in SIV-infected SMs, but not RMs, the level of proliferation of BM-based CD4+ T cells is higher than that of circulating CD4+ T cells. Interestingly, limited BM-based CD4+ T-cell proliferation was found in SIV-infected SMs with low CD4+ T-cell counts, suggesting a regenerative failure in these animals. Collectively, these results indicate that BM is involved in maintaining T-cell homeostasis in primates and suggest a role for BM-based CD4+ T-cell proliferation in determining the benign nature of natural SIV infection of SMs.
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Azevedo, Rita I., Maria Vieira D. Soares, João T. Barata, Rita Tendeiro, Ana Serra-Caetano, Rui M. M. Victorino, and Ana E. Sousa. "IL-7 sustains CD31 expression in human naive CD4+ T cells and preferentially expands the CD31+ subset in a PI3K-dependent manner." Blood 113, no. 13 (March 26, 2009): 2999–3007. http://dx.doi.org/10.1182/blood-2008-07-166223.
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Abstract The CD31+ subset of human naive CD4+ T cells is thought to contain the population of cells that have recently emigrated from the thymus, while their CD31− counterparts have been proposed to originate from CD31+ cells after homeostatic cell division. Naive T-cell maintenance is known to involve homeostatic cytokines such as interleukin-7 (IL-7). It remains to be investigated what role this cytokine has in the homeostasis of naive CD4+ T-cell subsets defined by CD31 expression. We provide evidence that IL-7 exerts a preferential proliferative effect on CD31+ naive CD4+ T cells from adult peripheral blood compared with the CD31− subset. IL-7–driven proliferation did not result in loss of CD31 expression, suggesting that CD31+ naive CD4+ T cells can undergo cytokine-driven homeostatic proliferation while preserving CD31. Furthermore, IL-7 sustained or increased CD31 expression even in nonproliferating cells. Both proliferation and CD31 maintenance were dependent on the activation of phosphoinositide 3-kinase (PI3K) signaling. Taken together, our data suggest that during adulthood CD31+ naive CD4+ T cells are maintained by IL-7 and that IL-7–based therapies may exert a preferential effect on this population.
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Surh, Charles D. "Homeostasis of Mature T Cells." Blood 112, no. 11 (November 16, 2008): sci—24—sci—24. http://dx.doi.org/10.1182/blood.v112.11.sci-24.sci-24.
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Abstract The overall size and composition of the mature T cell pool is regulated by homeostatic mechanisms. A hallmark of homeostatic regulation is the ability of the T cells to undergo spontaneous “homeostatic” proliferation in response to severe lymphopenia. By defining the factors that drive such homeostatic proliferation, we have determined that homeostasis of naïve and memory T cells is controlled by signals from contact with self-MHC/peptide ligands and/or two cytokines, namely IL-7 and IL-15. In addition, we have recently described a simple and highly effective way to administer IL-2, IL-7, IL-15, and other cytokines to strongly expand selective populations of T cell under normal physiological conditions. This new approach overcomes the current limitations that prevent therapeutic use of these essential T cell regulators in their native form. Identification of these homeostatic factors has already proven to be highly clinically relevant in devising novel therapeutic modalities for treatment of cancer and restoration of the immune deficiency from lympho-depleting regiments and advanced aging. The new method of delivering exogenous cytokines should further expand the clinical applicability of homeostatic cytokines.
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Guo, Fukun, David Hildeman, Jun Mo, and Yi Zheng. "Gene Targeting of Cdc42 Reveals Its Essential Role in T Cell Development and Homeostasis." Blood 110, no. 11 (November 16, 2007): 794. http://dx.doi.org/10.1182/blood.v110.11.794.794.
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Abstract Cdc42 of the Rho GTPase family is known to play an essential role in diverse cell functions. Previous studies by using dominant mutants or transgenic mice suggest that Cdc42 is involved in T cell polarization, immune synapse formation, migration, and development. Because the dominant mutant overexpressing approach imposes significant experimental limitations, we have characterized the T cell-specific, conditional gene targeted mice with the Lck-Cre;Cdc42loxP/loxP genotype in an effort to define the physiological role of Cdc42. Firstly, Cdc42 gene disruption in T cells caused an increase of CD4+CD8+ double positive T cells by ∼10% whereas a reduction of both CD4+CD8− and CD4−CD8+ single positive T cells by >50% in the Cdc42−/ − thymus. The thymus of Cdc42-deleted mice showed small and inconspicuous thymic medulla and the thymic cortex of Cdc42-deficient mice appeared prominent. Examination of CD69 expression in Cdc42−/ − CD4+CD8+ T cells revealed a defective positive selection. In peripheral organs, loss of Cdc42 caused a drastic reduction of mature T cell populations in lymph nodes, blood and spleens. Spleens of the Cdc42 null mice contained ∼1/7 of CD4+ T cells and ∼1/8 of CD8+ T cells compared with that of wild type (WT) mice. These phenotypic observations indicate that Cdc42 regulates T cell development and homeostasis. Secondly, the perturbed T cell homeostasis in Cdc42 null mice is associated with defective T cell survival characterized by an increase in apoptosis and a gain of resistance to IL-7-mediated cell survival. The apoptotic phenotype of Cdc42−/ − T cells correlates with an increased expression of pro-apoptotic Fas and decreased expression of anti-apoptotic BCL-2. Concomitantly, Cdc42 deficiency resulted in an increase in homeostatic proliferation as manifested by increased in vivo BrdU incorporation in Cdc42-deficient T cells and accelerated division of Cdc42 null cells upon adoptive transfer into Rag2−/ − mice, possibly due to a compensatory effect of lymphopenia. Thus, a combined effect on survival and proliferation by Cdc42 deficiency may contribute to the defective T cell homeostasis. Thirdly, F-actin assembly, T cell receptor (TCR) capping, and cell migration were impaired in T cells lacking Cdc42. Cdc42 deficiency caused a ∼50% reduction in the percentage of CD4+ T cells with capped TCR in response to TCR cross-linking. Chemotaxis of Cdc42−/ − CD4+ T cells toward SDF-1a was reduced by 40% in comparison with that of WT cells, suggesting that Cdc42 regulates T cell migration and polarization, which may also be involved in the defective homeostatic distribution of Cdc42−/ − T cells. Fourthly, Cdc42 deficiency appears to promote the activation of mature T cells with an elevated expression of a T cell activation marker, CD69. Cdc42−/ − T cells proliferated faster than WT cells and showed increased BrdU incorporation upon in vitro culture with CD3 antibody. This activation phenotype may be attributed to a constitutively elevated ERK activity found in the Cdc42−/ − T cells. Finally, loss of Cdc42 led to an increase of naturally-occurring and the lymphocytic choriomeningitis virus-specific effector and memory T cells. Autoimmune-protective CD4+CD25+ regulatory T cells were markedly reduced and the production of T helper cell-dependent IgG2a increased by ∼6 folds in the absence of Cdc42. Taken together, our results suggest that Cdc42 plays a critical role in T cell homeostasis by regulating survival and proliferation. Further, Cdc42 is important for T cell actin cytoskeleton rearrangement, polarization and migration and for effector and memory T cell response.
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Zhang, Baojun, Qingzhu Jia, Cheryl Bock, Gang Chen, Haili Yu, Qingshan Ni, Ying Wan, Qijing Li, and Yuan Zhuang. "Glimpse of natural selection of long-lived T-cell clones in healthy life." Proceedings of the National Academy of Sciences 113, no. 35 (August 17, 2016): 9858–63. http://dx.doi.org/10.1073/pnas.1601634113.
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Homeostatic maintenance of T cells with broad clonal diversity is influenced by both continuing output of young T cells from the thymus and ongoing turnover of preexisting clones in the periphery. In the absence of infection, self and commensal antigens are thought to play important roles in selection and homeostatic maintenance of the T-cell pool. Most naïve T cells are short-lived due to lack of antigen encounter, whereas antigen-experienced T cells may survive and persist as long-lived clones. Thus far, little is known about the homeostasis, antigenic specificity, and clonal diversity of long-lived T-cell clones in peripheral lymphoid organs under healthy living conditions. To identify long-lived T-cell clones in mice, we designed a lineage-tracing method to label a wave of T cells produced in the thymus of young mice. After aging the mice for 1.5 y, we found that lineage-tracked T cells consisted of primarily memory-like T cells and T regulatory cells. T-cell receptor repertoire analysis revealed that the lineage-tracked CD4 memory-like T cells and T regulatory cells exhibited age-dependent enrichment of shared clonotypes. Furthermore, these shared clonotypes were found across different mice maintained in the same housing condition. These findings suggest that nonrandom and shared antigens are involved in controlling selection, retention, and immune tolerance of long-lived T-cell clones under healthy living conditions.
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Saini, Manoj, Claire Pearson, and Benedict Seddon. "Regulation of T cell-dendritic cell interactions by IL-7 governs T-cell activation and homeostasis." Blood 113, no. 23 (June 4, 2009): 5793–800. http://dx.doi.org/10.1182/blood-2008-12-192252.
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Abstract Interleukin-7 (IL-7) plays a central role in the homeostasis of the T-cell compartment by regulating T-cell survival and proliferation. Whether IL-7 can influence T-cell receptor (TCR) signaling in T cells remains controversial. Here, using IL-7–deficient hosts and TCR-transgenic T cells that conditionally express IL-7R, we examined antigen-specific T-cell responses in vitro and in vivo to viral infection and lymphopenia to determine whether IL-7 signaling influences TCR-triggered cell division events. In vitro, we could find no evidence that IL-7 signaling could costimulate T-cell activation over a broad range of conditions, suggesting that IL-7 does not directly tune TCR signaling. In vivo, however, we found an acute requirement for IL-7 signaling for efficiently triggering T-cell responses to influenza A virus challenge. Furthermore, we found that IL-7 was required for the enhanced homeostatic TCR signaling that drives lymphopenia-induced proliferation by a mechanism involving efficient contacts of T cells with dendritic cells. Consistent with this, saturating antigen-presenting capacity in vivo overcame the triggering defect in response to cognate peptide. Thus, we demonstrate a novel role for IL-7 in regulating T cell–dendritic cell interactions that is essential for both T-cell homeostasis and activation in vivo.
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Alves, Nuno L., Berend Hooibrink, Fernando A. Arosa, and René A. W. van Lier. "IL-15 induces antigen-independent expansion and differentiation of human naive CD8+ T cells in vitro." Blood 102, no. 7 (October 1, 2003): 2541–46. http://dx.doi.org/10.1182/blood-2003-01-0183.
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Abstract Recent studies in mice have shown that although interleukin 15 (IL-15) plays an important role in regulating homeostasis of memory CD8+ T cells, it has no apparent function in controlling homeostatic proliferation of naive T cells. We here assessed the influence of IL-15 on antigen-independent expansion and differentiation of human CD8+ T cells. Both naive and primed human T cells divided in response to IL-15. In this process, naive CD8+ T cells successively down-regulated CD45RA and CD28 but maintained CD27 expression. Concomitant with these phenotypic changes, naive cells acquired the ability to produce interferon γ (IFN-γ) and tumor necrosis factor α (TNF-α), expressed perforin and granzyme B, and acquired cytotoxic properties. Primed CD8+ T cells, from both noncytotoxic (CD45RA-CD27+) and cytotoxic (CD45RA+CD27-) subsets, responded to IL-15 and yielded ample numbers of cytokine-secreting and cytotoxic effector cells. In summary, all human CD8+ T-cell subsets had the ability to respond to IL-15, which suggests a generic influence of this cytokine on CD8+ T-cell homeostasis in man. (Blood. 2003;102:2541-2546)
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Stonier, Spencer W., Lisa J. Ma, Eliseo F. Castillo, and Kimberly S. Schluns. "Dendritic cells drive memory CD8 T-cell homeostasis via IL-15 transpresentation." Blood 112, no. 12 (December 1, 2008): 4546–54. http://dx.doi.org/10.1182/blood-2008-05-156307.
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AbstractInterleukin-15 (IL-15) is crucial for the development of naive and memory CD8 T cells and is delivered through a mechanism called transpresentation. Previous studies showed that memory CD8 T cells require IL-15 transpresentation by an as yet unknown cell of hematopoietic origin. We hypothesized that dendritic cells (DCs) transpresent IL-15 to CD8 T cells, and we examined this by developing a transgenic model that limits IL-15 transpresentation to DCs. In this study, IL-15 transpresentation by DCs had little effect on restoring naive CD8 T cells but contributed to the development of memory-phenotype CD8 T cells. The generation of virus-specific, memory CD8 T cells was partially supported by IL-15Rα+ DCs through the preferential enhancement of a subset of KLRG-1+CD27− CD8 T cells. In contrast, these DCs were largely sufficient in driving normal homeostatic proliferation of established memory CD8 T cells, suggesting that memory CD8 T cells grow more dependent on IL-15 transpresentation by DCs. Overall, our study clearly supports a role for DCs in memory CD8 T-cell homeostasis but also provides evidence that other hematopoietic cells are involved in this function. The identification of DCs fulfilling this role will enable future studies to better focus on mechanisms regulating T-cell homeostasis.
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Lu, Ning, Yui-Hsi Wang, and Yong-Jun Liu. "TSLP and IL-7 use two different mechanisms in regulating human CD4+ T cell homeostasis (82.1)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 82.1. http://dx.doi.org/10.4049/jimmunol.182.supp.82.1.
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Abstract Homeostatic proliferation of CD4+ T cells depends on both self-peptide-MHC ligands and cytokines such as interleukin 7 (IL-7) and Thymic Stromal Lymphopoietin (TSLP). Although it is well established that IL-7 directly acts on CD4+ T cells, data on whether TSLP directly induce human CD4+ T cell proliferation and TH2 differentiation are conflicting. We report here that resting and activated CD4+ T cells express high levels of IL-7 receptors, but very low levels of TSLP receptor when compared with that expressed by myeloid dendritic cells (mDC). While IL-7 induce strong STAT1, 3 and 5 activation and promote the proliferation of naïve CD4+ T cells in the presence of anti-CD3 and anti-CD28, TSLP only induce a weak STAT5 activation which is associated with the marginally improved cell survival, but fail to induce CD4+ T cell proliferation and TH2 differentiation. The effect of TSLP on enhancing human T cell proliferation could be observed only when sorted naïve CD4+ T cells were cultured with contaminated mDCs at as low as 0.5% in culture. TSLP could only induce purified naïve CD4+ T cells to differentiate into TH2 cells in the presence allogeneic mDCs. This study demonstrates that IL-7 and TSLP use different mechanisms in regulating human CD4+ T cell homeostasis and underscores the importance of cell purity in immunology research. Key words: interleukin 7, Thymic Stromal Lymphopoietin, T cell homeostasis, proliferation, survival
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Costanzo, Anne, Kristen Taylor, Peggy Han, Ken Fujioka, and Julie Jameson. "Altered human γδ peripheral blood lymphocyte homeostasis and impaired influenza A viral response in obesity (168.9)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 168.9. http://dx.doi.org/10.4049/jimmunol.188.supp.168.9.
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Abstract Obesity is an independent risk factor for severe and fatal influenza infection. Little is known about how obesity impacts influenza-specific T cell responses in humans. In healthy adults, γδ T cells are the major circulating population of T cells that rapidly respond to influenza virus infected APCs. The majority express a Vγ9Vδ2 TCR that recognizes phosphoantigens expressed by infected or transformed cells. To determine whether this anti-viral T cell population was impacted by obesity, human peripheral blood mononuclear cells were isolated from non-obese and obese donors and analyzed for homeostatic T cell numbers and function. We found the percentage of Vγ9Vδ2 T cells negatively correlates with increased body mass index (BMI), suggesting the severity of obesity impacts γδ T cell homeostasis. Furthermore, Vγ9Vδ2 T cells exhibit a skewed maturation, with a higher propensity toward a unique γδ T effector CD45RA+ memory cell population. We have identified that obese patients show reduced expression of the homing molecule CCR5 on γδ T cells as well as reduced IFN-γ and TNF-α production in response to influenza infection. This blunted Vγ9Vδ2 T cell response in obese patients is T cell intrinsic as function can be rescued using a strong TCR agonist. Our data show that one arm of the antiviral immune response to influenza is compromised by obesity. These studies support the concept that therapies should be developed to restore immune homeostasis in obese patients.
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Jameson, Stephen C. "T cell homeostasis: Keeping useful T cells alive and live T cells useful." Seminars in Immunology 17, no. 3 (June 2005): 231–37. http://dx.doi.org/10.1016/j.smim.2005.02.003.
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Zhao, Luming, Shaomin Hu, Micha L. Davila, and Na Xiong. "Intestine-specific CCR10+ plasma cells regulate migration of intestinal regulatory T cells." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 172.7. http://dx.doi.org/10.4049/jimmunol.200.supp.172.7.
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Abstract In intestines, B cells are activated in gut-associated lymphoid tissue (GALT) to differentiate predominantly to IgA antibody-secreting cells (IgA-ASCs), which acquire a CCR10+ specific gut-homing property and migrate into intestinal lamina propria where they secrete IgA antibodies specifically acting on commensal bacteria and food-borne antigens for homeostatic regulation. While IgA antibodies were extensively investigated, differentiation of B cells and their functional mechanisms in establishment of intestinal homeostasis are still incompletely understood. We herein report a novel process in which CCR10+ differentiated B cells regulate intestinal homeostasis. We found that CCR10+ IgA-ASCs preferentially interact with activated regulatory T (Treg) cells in GALT and lamina propria to help their localization in colons. In CCR10-knockout mice, defective intestinal migration of IgA-ASCs resulted in reduced Treg cells and spontaneous development of inflammatory symptoms in colons. In addition, in IgA-deficient mice, there was preferential compensatory generation of CCR10+ IgG-ASCs that substituted CCR10+ IgA-ASCs to promote T cell homeostasis and regulate commensal bacteria in colons. The preferential compensatory generation of CCR10+ IgG-ASCs was also observed in IgA-deficient patients. These findings aid our understanding of B cell differentiation and functional mechanisms in intestinal homeostatic regulation.
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Kawahata, Kimito, Takeyuki Kanzaki, Mitsuru Imamura, Lisa Akahira, Kazuya Michishita, Makoto Dohi, and Kazuhiko Yamamoto. "Regulatory T cells in the control of T cell homeostasis." Inflammation and Regeneration 30, no. 6 (2010): 502–6. http://dx.doi.org/10.2492/inflammregen.30.502.
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Hu, Shaomin, Jie Yang, and Na Xiong. "CCR10 regulates intestinal immune homeostasis through regulating both Treg and Teff cells in the intestine (MUC2P.832)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 68.16. http://dx.doi.org/10.4049/jimmunol.192.supp.68.16.
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Abstract Intestinal immune homeostasis is an active process of balanced tolerant responses towards the gut-resident commensals and other food-born stimulations. Failure of the balanced response could lead to inflammatory diseases and cancers. Understanding molecular mechanisms that differentially regulate the homeostatic vs. inflammatory activation of T cells are fundamentally important in the intestinal immunity. CCR10, through interaction with its mucosa-specific ligand CCL28, was previously found important in regulation of IgA antibody-producing B cells in intestines. On the other hand, CCR10 was suggested to be a skin- but not gut- homing molecule for T cells. Using a novel strain of CCR10-knockout/EGFP-knockin mouse, we found that CCR10 is specifically induced on activating T cells in healthy intestines in situ and is critically important in balanced maintenance and functions of Treg and Teff cells to promote the intestinal homeostasis. On the other hand, during intestinal immune activations associated with infection or other inflammatory stimulations, the induction of CCR10 on activated intestinal T cells were suppressed that allows the T cell activation along different lineages. Our findings represent the first demonstration that a chemokine receptor is specifically associated with the homeostatic status of the intestine and reveal that there exists an auto-promoting feedback circuit of intestinal homeostasis in which the CCR10/ligand axis are a critical molecular link.
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Schnell, Alexandra, Linglin Huang, Meromit Singer, Anvita Singaraju, Alina Bollhagen, Pratiksha I. Thakore, Danielle Dionne, et al. "Single-cell clonotype tracing of tissue Th17 cells during CNS autoimmunity reveals the conversion of intestinal homeostatic cells to pathogenic cells." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 61.11. http://dx.doi.org/10.4049/jimmunol.206.supp.61.11.
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Abstract At homeostasis, most Th17 cells are found in the lamina propria of the intestine, where they contribute to tissue homeostasis by inhibiting microbiota from tissue invasion and promote barrier functions. Recent studies in humans and mice have implicated intestinal Th17 cells in extra-intestinal autoimmune diseases, including multiple sclerosis, but the mechanism in which intestinal Th17 cells mediate these dichotomous functions remains unknown. Here, we combined single-cell RNA- and TCR-seq (scRNA/TCR-seq) with fate mapping of tissue Th17 cells to profile over 84,000 tissue Th17 cells and characterize their heterogeneity, plasticity, and migration at homeostasis and during CNS autoimmunity. We discovered a homeostatic Th17 cell population, that is induced by the intestinal microbiota, is present in both lymphoid organs and the intestine, and expresses IL-17. Joint scRNA- and TCR-seq showed that during EAE this homeostatic population gives rise to a pathogenic Th17 cell population, that migrates specifically through the draining lymph nodes and the spleen to the CNS, and highly expresses GM-CSF and IFNγ, but expresses little or low levels of IL-17. This conversion of homeostatic Th17 cells into encephalitogenic Th17 cells depended on IL-23R signaling. Our work characterizes Th17 heterogeneity, plasticity, and migration during homeostasis and CNS autoimmune disease, identifies a mechanism by which intestinal Th17 cells influence the generation of an autoimmune disease-inducing population, and provides further evidence for a direct relationship between the IL-17-producing and GM-CSF- and IFNγ- producing pathogenic T cells.
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Abdelsamed, Hossam Aly. "Human memory CD8 T cell effector potential is epigenetically preserved during in vivo homeostasis." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 144.7. http://dx.doi.org/10.4049/jimmunol.198.supp.144.7.
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Abstract Maintenance of memory CD8 T cell quantity and quality through antigen-independent homeostatic proliferation is vital for sustaining long-lived T cell-mediated immunity, yet the underlying mechanisms that preserve memory T cell functions during homeostasis remain largely unexplored. Here we show that preservation of effector-potential among human memory CD8 T cells during in vitro and in vivo homeostasis is coupled to maintenance of memory-associated DNA methylation programs. Whole-genome bisulfite sequencing of primary human naïve, short-lived effector memory (Tem), and longer-lived central memory (Tcm) and stem cell memory (Tscm) CD8 T cells identified demethylated promoters of effector molecules that are poised for rapid expression among all memory cell subsets. Effector-loci demethylation was heritably preserved during IL-7 and IL-15 mediated in vitro cell proliferation. In contrast to the effector-potential, antigen-independent proliferation induced a phenotypic conversion of Tcm and Tscm memory cells into Tem cells that was coupled to increased methylation of the CCR7 locus. Furthermore, in vivo proliferation of haploidentical donor memory CD8 T cells in lymhodepleted recipients resulted in a similar preservation of effector-associated methylation programs while enriching for Tem-associated programs. These data demonstrate that long-lived human memory CD8 T cells retain the ability to undergo antigen-independent epigenetic reprogramming during their developmental conversion into other memory subsets while at the same time preserving the poised effector state utilized by all memory T cells.
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Cekic, Caglar, Duygu Sag, and Joel Linden. "Cell-intrinsic adenosine A2A receptor signaling is required for T cell homeostasis and control of tumor growth (47.1)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 47.1. http://dx.doi.org/10.4049/jimmunol.188.supp.47.1.
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Abstract Adenosine generated as a result of normal metabolic activity is elevated in response to tissue stress, damage, or hypoxia. By stimulating adenosine A2A receptors (A2ARs) adenosine links metabolic activity to regulation of normal physiological functions such as sleep, blood flow, and inflammation. Although stimulation of A2ARs on activated T cells and APCs acutely suppresses inflammation and immune killing of tumor cells, global A2AR deletion has variable effects on the growth rate of syngeneic tumors, suggesting that A2AR signaling has opposing effects on immune function. Here we show that A2ARs are required for homeostatic maintenance of naïve T cells. In global A2AR-deficient mice naïve T cells undergo apoptosis, which drastically lower their number in blood and in peripheral lymph nodes. Lymphoid deletion of A2ARs, adoptive co-transfer and mixed bone-marrow reconstitution experiments showed that cell intrinsic A2AR signaling is required for T cell homeostasis. A2AR signaling is also required for interleukin 7 to optimally facilitate T cell survival ex vivo. In mice injected with syngeneic melanoma cells, lymphoid-specific A2AR deletion decreases T cell numbers in the periphery and in the tumor, reduces the proportion of tumor infiltrating T cells with an activated/memory phenotype, and markedly accelerates tumor growth. The results indicate that homeostatic adenosine production and A2AR signaling are required in naïve T cell maintenance and immune defense against tumors.
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Papatriantafyllou, Maria. "Maintaining T cell homeostasis." Nature Reviews Immunology 13, no. 8 (July 19, 2013): 547. http://dx.doi.org/10.1038/nri3504.
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Balakrishnan, Amritha, Burhan Jama, and Gerald P. Morris. "Endogenous Secondary TCRs Promote Homeostatic Advantage Via Recognition of Self-Antigens." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 215.9. http://dx.doi.org/10.4049/jimmunol.198.supp.215.9.
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Abstract Our laboratory studies how non-thymically selected secondary TCRs contribute to the T cell repertoire. We have previously demonstrated that peripheral T cells naturally expressing 2 TCRs have increased response to autoantigens. We hypothesized that this could promote homeostatic proliferation of T cells expressing 2 TCRs, which may cause autoimmune risk. To examine secondary TCRs in homeostasis, we performed competitive transfers of CFSE-labeled T cells from B6.Ly5.1 and B6.TCRα+/−.Thy1.1 (lacking secondary TCRs) into irradiated B6 recipients. T cells injected at a 1:1 ratio demonstrated a disadvantage for TCRα+/− T cells in lymphopenia-induced proliferation (LIP), with TCRα+/−/wt donor cell ratios of 0.6±0.1 at 8 d after transfer and 0.5±0.4 at 28 d after transfer. T cell population skewing resulted from increased proliferation of wild-type cells. The homeostatic advantage of secondary TCRs was less in chronic LIP (cLIP) (transfer into TCRα-knockout mice), with TCRα+/−/wt donor cell ratios of 0.8±0.3 at 8 d after transfer and 0.7±0.3 at 28 d after transfer. There was no difference between wt and TCRα+/− T cells in proliferative response to stimulation via anti-CD3/CD28, nor were differences observed for expression of CD3, CD5, or CD127. LIP and cLIP depend on signaling through the TCR, though reactivity to self-antigens is thought to drive LIP as opposed to endogenous antigens from commensal microflora in cLIP. Our results suggest that the advantage for secondary TCRs in homeostatic expansion reflects increased ability to interact with self-pMHC antigens. Current effort is focused to understand how this affects protective and autoreactive peripheral T cell repertoires during aging or iatrogenic lymphopenia.
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Shirakawa, Kohsuke, and Motoaki Sano. "T Cell Immunosenescence in Aging, Obesity, and Cardiovascular Disease." Cells 10, no. 9 (September 15, 2021): 2435. http://dx.doi.org/10.3390/cells10092435.
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Although advances in preventive medicine have greatly improved prognosis, cardiovascular disease (CVD) remains the leading cause of death worldwide. This clearly indicates that there remain residual cardiovascular risks that have not been targeted by conventional therapies. The results of multiple animal studies and clinical trials clearly indicate that inflammation is the most important residual risk and a potential target for CVD prevention. The immune cell network is intricately regulated to maintain homeostasis. Ageing associated changes to the immune system occurs in both innate and adaptive immune cells, however T cells are most susceptible to this process. T-cell changes due to thymic degeneration and homeostatic proliferation, metabolic abnormalities, telomere length shortening, and epigenetic changes associated with aging and obesity may not only reduce normal immune function, but also induce inflammatory tendencies, a process referred to as immunosenescence. Since the disruption of biological homeostasis by T cell immunosenescence is closely related to the development and progression of CVD via inflammation, senescent T cells are attracting attention as a new therapeutic target. In this review, we discuss the relationship between CVD and T cell immunosenescence associated with aging and obesity.
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Agenès, Fabien, Jean-Pierre Dangy, and Jörg Kirberg. "T cell receptor contact to restricting MHC molecules is a prerequisite for peripheral interclonal T cell competition." Journal of Experimental Medicine 205, no. 12 (November 17, 2008): 2735–43. http://dx.doi.org/10.1084/jem.20070467.
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T cell survival and homeostatic proliferation in the periphery requires T cell receptor (TCR) binding to restricting major histocompatability complex (MHC)−encoded molecules, as well as the availability of certain lymphokines. However, the exact mechanisms by which these signals interrelate and contribute to homeostasis are not understood. By performing T cell transfers into TCR transgenic hosts we detected a hierarchical order of homeostatic proliferation for T cells differing in MHC restriction, such that OT1 cells (Kb restricted) proliferated in P14 (Db-restricted TCR) recipients, but not vice versa. Using Kb mutant mice, we demonstrated that proliferation of OT1 cells in P14 recipients, as well as the ability of host OT1 cells to hinder the proliferation of donor P14 cells, were dependent on OT1-TCR binding to Kb molecules. However, interclonal T cell competition was not mediated simply by competition for physical access to the MHC-bearing cell. This was shown in parabiotic pairs of OT1 and Kb mutant mice in which P14 cells failed to proliferate, even though the OT1 cells could not interact with half of the APCs in the system. Thus, we conclude that the interaction between the TCR and restricting MHC molecule influences the ability to compete for trophic resources not bound to the stimulating APC. This mechanism allows a local competitiveness that extends beyond a T cell's specificity.
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Pino, Maria, Susan Pereira Ribeiro, Amélie Pagliuzza, Khader Ghneim, Anum Khan, Emily Ryan, Justin L. Harper, et al. "Increased homeostatic cytokines and stability of HIV-infected memory CD4 T-cells identify individuals with suboptimal CD4 T-cell recovery on-ART." PLOS Pathogens 17, no. 8 (August 27, 2021): e1009825. http://dx.doi.org/10.1371/journal.ppat.1009825.
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Clinical outcomes are inferior for individuals with HIV having suboptimal CD4 T-cell recovery during antiretroviral therapy (ART). We investigated if the levels of infection and the response to homeostatic cytokines of CD4 T-cell subsets contributed to divergent CD4 T-cell recovery and HIV reservoir during ART by studying virologically-suppressed immunologic responders (IR, achieving a CD4 cell count >500 cells/μL on or before two years after ART initiation), and virologically-suppressed suboptimal responders (ISR, did not achieve a CD4 cell count >500 cells/μL in the first two years after ART initiation). Compared to IR, ISR demonstrated higher levels of HIV-DNA in naïve, central (CM), transitional (TM), and effector (EM) memory CD4 T-cells in blood, both pre- and on-ART, and specifically in CM CD4 T-cells in LN on-ART. Furthermore, ISR had higher pre-ART plasma levels of IL-7 and IL-15, cytokines regulating T-cell homeostasis. Notably, pre-ART PD-1 and TIGIT expression levels were higher in blood CM and TM CD4 T-cells for ISR; this was associated with a significantly lower fold-changes in HIV-DNA levels between pre- and on-ART time points exclusively on CM and TM T-cell subsets, but not naïve or EM T-cells. Finally, the frequency of CM CD4 T-cells expressing PD-1 or TIGIT pre-ART as well as plasma levels of IL-7 and IL-15 predicted HIV-DNA content on-ART. Our results establish the association between infection, T-cell homeostasis, and expression of PD-1 and TIGIT in long-lived CD4 T-cell subsets prior to ART with CD4 T-cell recovery and HIV persistence on-ART.
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Li, ShuShun, David A. Hildeman, H. Leighton Grimes, David A. Williams, and Yi Gu. "T Cell Lymphopenia in Rhoh−/− Mice Results from Combined Defects of T Cell Migration and IL-7-Regulated Naïve T Cell Homeostasis." Blood 108, no. 11 (November 16, 2006): 872. http://dx.doi.org/10.1182/blood.v108.11.872.872.
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Abstract The Rho family GTPases are increasingly implicated for their important roles in T cell development and function. We have found that RhoH, a hematopoietic-specific member of this family is essential for thymocyte development (Gu et al, Nat Immunol, in press). Further, Rhoh−/− mice showed T cell lymphopenia. In particular, naïve T cells were reduced in secondary lymphoid organs and blood both in unchallenged and LCMV-challenged Rhoh−/− mice compared to WT controls. These findings suggest a possible defect in T cell emigration from thymus and peripheral T cell homeostasis in Rhoh−/− mice. To study the role(s) of RhoH in T cell migration and homeostasis, purified splenic T cells were adoptively transferred into common γ−/−; Rag2−/− mice. T cells were then recovered from spleens 3d and 8d post-transplantation. The recovery of Rhoh−/− T cells was decreased by 60% compared with WT cells. In vitro migration of Rhoh−/− T cells towards SDF-1α, a homeostatic chemokine for T cells, in a transwell migration assay was significantly reduced compared to WT cells. Flow analysis showed decreased number of CXCR4 expressing and reduced expression levels of CXCR4 on Rhoh−/− T cells. Furthermore, apoptotic T cells were increased twofold in Rhoh−/− mice compared to controls. CFSE staining of adoptively transferred T cells demonstrated a comparable proliferation rate between Rhoh−/− and WT cells in the recipient mice. Our data suggest that RhoH plays an important role in T cell homeostasis via regulating cell survival and SDF-1α-mediated migration. To further investigate how RhoH regulates T cell survival, we focused on IL-7, an essential factor for prolonged survival of naïve T cells. One way IL-7 exerts its effect is through upregulating the Bcl-2 family of antiapoptotic proteins. Our data showed that in vitro survival of Rhoh−/− T cells in response to IL-7 was impaired, and expression of IL-7Rα and Bcl-2 were both decreased in Rhoh−/− T cells. To further study a potential role of RhoH in regulation of IL-7R expression, FACsvantage sorted naïve T cells (CD4+CD44low, or CD8+CD44low) were cytokine starved overnight, then cultured with or without the addition of IL-7 for 6 hrs, and analyzed for IL-7Rα expression by flow cytometry. In WT cells, during cytokine starvation CD4 and a subset of CD8 naïve cells upregulated IL-7Rα expression, but this upregulation was reduced followed IL-7 stimulation. In contrast, Rhoh−/− T cells failed to show either up- or subsequent down-regulation of IL-7Rα in response to cytokine starvation and IL-7 exposure. These data may indicate a role for RhoH in regulating IL-7R expression in naïve CD4 T cells. Taken together, these findings suggest that RhoH is required for IL-7-mediated T cell survival and SDF-1α-mediated homing and/or emigration from thymus. Thus, deficiency of naïve T cells in Rhoh−/− mice likely results from combined defects in T cell migration and homeostasis.
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Gubbels Bupp, Melanie, Seth Litvin, and Victoria Robinson. "The forkhead transcription factor, Foxo1, fine-tunes sensitivity to homeostatic signals during calorie restriction in CD8+ cytotoxic T cells (P1292)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 119.5. http://dx.doi.org/10.4049/jimmunol.190.supp.119.5.
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Abstract In addition to longevity enhancement, calorie restriction has been reported to slow the appearance of aging-related T cell abnormalities. However, the molecular mechanism underlying this phenomenon is ill-defined. We report that short-term calorie restriction in mice conferred protection to naïve CD8+ T cells from death-by-neglect, as compared to cells isolated from mice fed ad libitum. An ortholog of the forkhead transcription factor, Foxo1, is required for the longevity benefits of calorie restriction in C. elegans. Therefore, mice with a conditional, T cell-specific deficiency of Foxo1 were also subjected to calorie restriction. Calorie restriction in the absence of Foxo1 did not result in reduced naïve CD8+ T cell death by neglect. Naïve CD8+ T cells isolated from calorie restricted mice express higher levels of the cell surface receptors, CD8 and CD127, both of which are responsible for receiving homeostatic survival signals in vivo. Thus, Foxo1 coordinates an intrinsic transcriptional response to calorie restriction that alters the sensitivity of naïve CD8+ T cells to homeostatic signals. Additional studies revealed that full calorie restriction (as opposed to restricting one component of the diet) is required for this phenomenon. To our knowledge, Foxo1 is the first transcription factor identified to contribute to altered naïve CD8+ T cell homeostasis during calorie restriction in mice.
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Ranson, Thomas, Christian A. J. Vosshenrich, Erwan Corcuff, Odile Richard, Werner Müller, and James P. Di Santo. "IL-15 is an essential mediator of peripheral NK-cell homeostasis." Blood 101, no. 12 (June 15, 2003): 4887–93. http://dx.doi.org/10.1182/blood-2002-11-3392.
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Abstract Several distinct classes of surface receptors can, on ligand binding, transmit signals that modulate the survival, proliferation, and apoptosis of peripheral B, T, and natural killer (NK) cells. At the population level, dynamic changes in lymphocyte cell numbers are strictly regulated to maintain a steady state, a process referred to as homeostasis. Although several studies have investigated the signals that regulate B- and T-cell homeostasis, little is known about the mechanisms that control the survival and proliferation of peripheral NK cells. Using an adoptive transfer system, we have investigated the role of γc-dependent cytokines, in particular interleukin 7 (IL-7) and IL-15, and major histocompatibility complex (MHC) class I molecules in peripheral NK-cell homeostasis. We observed that IL-15 plays a dominant role in the survival of peripheral NK cells, via maintenance of the antiapoptotic factor Bcl-2. IL-15 availability, however, also plays an important role because endogenous NK cells in the recipient mice influence the behavior of adoptively transferred NK cells. Finally, although NK cells bear functional inhibitory Ly49 receptors for MHC class I molecules, the presence or absence of specific ligands on host cells did not influence the survival or homeostatic expansion of donor NK cells.
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Huang, Gonghua, Yanyan Wang, and Hongbo Chi. "TAK1-dependent checkpoint in dendritic cell survival promotes immune homeostasis and function (111.53)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 111.53. http://dx.doi.org/10.4049/jimmunol.188.supp.111.53.
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Abstract Homeostatic control of dendritic cell (DC) survival is crucial for adaptive immunity, but the molecular mechanism is not well defined. Moreover, how DCs influence immune homeostasis under steady state remains unclear. Combining DC-specific and inducible deletion systems, we report that the kinase TAK1 is an essential regulator of DC survival and immune system homeostasis and function. Deficiency of TAK1 in CD11c+ cells induced markedly elevated apoptosis, leading to the depletion of DC populations, especially the CD8+ and CD103+ DC subsets in lymphoid and non-lymphoid tissues, respectively. TAK1 also contributed to DC development by promoting the generation of DC precursors. Pro-survival signals from Toll-like receptors, CD40 and RANK are integrated by TAK1 in DCs, which in turn mediated activation of downstream NFκ-B and AKT-Foxo pathways and established a gene-expression program. TAK1 deficiency in DCs caused a myeloid proliferative disorder characterized by expansion of neutrophils and inflammatory monocytes, disrupted T cell homeostasis, and prevented effective T cell priming and generation of regulatory T cells. Moreover, TAK1 signaling in DCs was required to prevent myeloid proliferation even in the absence of lymphocytes, indicating a previously unappreciated regulatory mechanism of DC-mediated control of myeloid cell-dependent inflammation. Therefore, TAK1 orchestrates a pro-survival checkpoint in DCs that affects the homeostasis and function of the immune system.
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Fry, Terry J., Manoj Sinha, Matthew Milliron, Yu-Waye Chu, Veena Kapoor, Ronald E. Gress, Elaine Thomas, and Crystal L. Mackall. "Flt3 ligand enhances thymic-dependent and thymic-independent immune reconstitution." Blood 104, no. 9 (November 1, 2004): 2794–800. http://dx.doi.org/10.1182/blood-2003-11-3789.
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Abstract Despite recent progress in our understanding of the biology of T-cell homeostasis, clinically available therapies to substantially improve immune reconstitution in patients sustaining T-cell depletion are lacking. T cells are regenerated via a dynamic interplay between thymopoiesis and thymic-independent homeostatic peripheral expansion (HPE). Using athymic mice subjected to T-cell depletion, we observed that HPE is critically dependent on dendritic cells (DCs) for presentation of antigen, raising the possibility that the availability of DCs might be limiting in vivo for HPE to occur efficiently. Indeed, flt3 ligand (flt3L) treatment of athymic mice subjected to T-cell depletion (without DC depletion) substantially enhanced HPE and improved immune competence. Following bone marrow transplantation (BMT) in athymic hosts, both dendritic cells and T cells were profoundly depleted and flt3L therapy restored DC numbers and enhanced HPE. In addition, thymus-bearing BMT recipients treated with flt3L regenerated increased numbers of thymic-dependent progeny with increased numbers of T-cell receptor excision circle (TREC)-positive T cells, indicating increased thymopoiesis. Therefore, flt3L is a potent immunorestorative agent that enhances both thymic-dependent and thymic-independent pathways of T-cell regeneration. (Blood. 2004;104:2794-2800)
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Abdelsamed, Hossam A., Ardiana Moustaki, Yiping Fan, Pranay Dogra, Hazem E. Ghoneim, Caitlin C. Zebley, Brandon M. Triplett, Rafick-Pierre Sekaly, and Ben Youngblood. "Human memory CD8 T cell effector potential is epigenetically preserved during in vivo homeostasis." Journal of Experimental Medicine 214, no. 6 (May 10, 2017): 1593–606. http://dx.doi.org/10.1084/jem.20161760.
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Antigen-independent homeostasis of memory CD8 T cells is vital for sustaining long-lived T cell–mediated immunity. In this study, we report that maintenance of human memory CD8 T cell effector potential during in vitro and in vivo homeostatic proliferation is coupled to preservation of acquired DNA methylation programs. Whole-genome bisulfite sequencing of primary human naive, short-lived effector memory (TEM), and longer-lived central memory (TCM) and stem cell memory (TSCM) CD8 T cells identified effector molecules with demethylated promoters and poised for expression. Effector-loci demethylation was heritably preserved during IL-7– and IL-15–mediated in vitro cell proliferation. Conversely, cytokine-driven proliferation of TCM and TSCM memory cells resulted in phenotypic conversion into TEM cells and was coupled to increased methylation of the CCR7 and Tcf7 loci. Furthermore, haploidentical donor memory CD8 T cells undergoing in vivo proliferation in lymphodepleted recipients also maintained their effector-associated demethylated status but acquired TEM-associated programs. These data demonstrate that effector-associated epigenetic programs are preserved during cytokine-driven subset interconversion of human memory CD8 T cells.
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French, J. D., C. L. Roark, W. K. Born, and R. L. O'Brien. "T cell homeostasis is established in competition with T cells and NK cells." Proceedings of the National Academy of Sciences 102, no. 41 (October 3, 2005): 14741–46. http://dx.doi.org/10.1073/pnas.0507520102.
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Tai, Tzong-Shyuan, Sung-Yun Pai, and I.-Cheng Ho. "GATA-3 regulates the development, homeostasis, and activation of CD8 T cells (160.20)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 160.20. http://dx.doi.org/10.4049/jimmunol.186.supp.160.20.
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Abstract GATA3 is a master transcription factor for the differentiation of T helper 2 (TH2) cells and also essential for CD4 T cell development. GATA-3 is expressed in CD8+ T cells, but its role in this subset of T cells is largely unknown. We have studied the development and function of CD8+ T cells in mice that are deficient in GATA-3 only in T cells (G3KO mice). Although the total number of TCRhi CD8SP thymocytes was normal, we found that these mice contained significantly fewer TCRhiCD24lo CD8SP thymocytes, indicating that GATA-3 is required for the final maturation step of CD8SP thymocytes. Despite the dramatic reduction in thymic output, G3KO mice developed lymphoadenopathy due to abnormal expansion of CD8+T and B cells. This abnormal expansion of G3KO CD8+T cells is mediated by a CD8+T cell-extrinsic mechanism. Paradoxically, G3KO CD8+T cells displayed a cell-intrinsic defect in homeostatic proliferation and were hyporesponsive to TCR stimulation. There was no apparent impairment in signal transduction downstream of TCR in G3KO CD8+T cells, suggesting that GATA-3 may modulate the activation threshold of CD8+ T cells. Taken together, our data demonstrate that GATA3 also plays a critical role in regulating the development, homeostasis, and activation of CD8+ T cell.
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Mailloux, Adam, and Pearlie Epling-Burnette. "Bioartificial collagen matrix limits IL-7 and IL-15-induced T-cell homeostatic proliferation without affecting T-cell receptor signaling (P1327)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 119.19. http://dx.doi.org/10.4049/jimmunol.190.supp.119.19.
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Abstract Intermittent homeostatic growth governed by STAT3/5-associated common γ chain (γc) cytokines IL-7 and IL-15 is the principal source of new T-cells after thymic involution. Lymphoproliferation, as seen in large granular lymphocyte leukemia and autoimmune lymphoproliferative syndrome (ALPS), results from failed anti-apoptotic and hyper IL-15 response. Contextual constraints in the microenvironment may also regulate homeostasis. Using primary human naïve and memory CD4+ and CD8+ T-cells, we found that bioartifical collagen matrix limits proliferation by IL-7 and IL-15, but not by anti-CD3/CD28. Flow cytometry was used to analyze collagen receptor expression on dividing T-cells. The expression of known activating collagen receptors, discoidin domain receptor (DDR)1, DDR2, and gpVI was not observed. However, the inhibitory collagen receptor, leukocyte associated IgG-like receptor-1 (LAIR-1), was increased with each cellular division, reaching 2-3 fold over non-dividing cells in response to IL-7 and IL-15. Such changes were not observed with anti-CD3/CD28 stimulation. Western blot analysis revealed no difference in cyclins, cyclin-dependant kinase (CDK)4, p21, p27, or STAT3/5 phosphorylation in collagen matrix, but did reveal reduced expression of the cell cycle regulator CDK6. These data provides rational for the future study of LAIR-1 in T-cell homeostasis and indicates that collagen adhesion may provide spatial repression from the microenvironment during homeostatic expansion.
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Jameson, Julie, Anne Costanzo, and Kristen Taylor. "Obesity compromises the ability of skin γδ T cells to regulate skin homeostasis and barrier function (166.6)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 166.6. http://dx.doi.org/10.4049/jimmunol.186.supp.166.6.
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Abstract Within the epidermis of the skin resides a unique population of γδ T lymphocytes that play key roles in skin homeostasis and wound repair. During obesity and related metabolic disease the skin-resident γδ T lymphocytes become dysfunctional due the chronic inflammatory environment. This dysfunction contributes to the non-healing wounds associated with disease. We are now investigating how skin γδ T cell dysfunction impacts normal keratinocyte homeostasis. Interestingly, in lean mice we have determined that the number of keratinocytes in the epidermis is directly proportional to the number of closely neighboring γδ T cells. Once obesity and related metabolic disease ensues, the keratinocyte numbers resemble areas that are devoid of γδ T cells in lean mice and keratinocytes are unable to maintain normal homeostatic numbers. Furthermore, keratinocytes in obese mice exhibit diminished proliferation and accelerated differentiation. This results in a dysregulated epidermis in which fewer basal keratinocytes express the proliferation marker keratin 5 and more exhibit early expression of the differentiation marker keratin 1. Additionally, skin γδ T cells downregulate CD103 in obese mice, while keratinocytes alter expression of its ligand E-cadherin. Together these studies demonstrate that dysfunctional γδ T cells in the epidermis of obese mice contribute to impaired keratinocyte homeostasis ultimately resulting in compromised skin barrier function.
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Mackall, Crystal L., Frances T. Hakim, and Ronald E. Gress. "Restoration of T-cell homeostasis after T-cell depletion." Seminars in Immunology 9, no. 6 (December 1997): 339–46. http://dx.doi.org/10.1006/smim.1997.0091.
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Xiao, Hui, Lei Shi, Xia Chen, Aiping Zang, Tiantian Li, and Jianbo Yang. "TSC1-mTOR-controlled metabolic-epigenetic crosstalk underlies DC control of CD8+ T cell homeostasis." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 56.4. http://dx.doi.org/10.4049/jimmunol.202.supp.56.4.
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Abstract Dendritic cells (DCs) play pivotal roles in T cell homeostasis and activation, and metabolic programing has been linked to DC development and function recently. However, the metabolic underpinnings corresponding to distinct DC functions remain largely unresolved. Here we demonstrate a special metabolic-epigenetic coupling mechanism orchestrated by TSC1-mTOR for the homeostatic DC function. Specific ablation of TSC1 in the DC compartment (TSC1DC-KO) largely preserved DC development, but led to pronounced reduction in naïve and memory-phenotype CD8+ T cells, a defect fully rescued by the simultaneous deletion of mTOR or Raptor in DCs. Moreover, TSC1DC-KO mice were unable to launch efficient antigen-specific CD8+ T effector responses required for containing Listeria monocytogenes and B16 melanomas. Mechanistically, our data suggest that steady-state DCs tune down de novo fatty acid synthesis through TSC1 and divert acetyl-CoA for histone acetylation. Correspondingly, TSC1-deficiency elevated ACC1 expression and fatty acid synthesis in the steady-state DCs, leading to impaired epigenetic imprinting on selective genes such as MHC-I and IL-7. Remarkably, tempering ACC1 activity was able to avert cytosolic acetyl-CoA for histone acetylation and restoration of the gene expression program compromised by TSC1-deficiency. Taken together, our results uncover a crucial role for TSC1-mTOR in metabolic programing the homeostatic DCs for T cell homeostasis, and implicate metabolic-coupled epigenetic imprinting as a paradigm for DC specification.