Macroautophagy (hereafter referred to as "autophagy") is a well-conserved catabolic process in eukaryotic cells. It is defined by the formation of double membrane autophagosome vesicles and functions in the intracellular degradation of cytosol and organelles. Although autophagy has long been recognized, its functions in various physiological and pathological processes have only begun to be elucidated. Our recent work has demonstrated that primary T lymphocytes have the capacity to undergo autophagy and that the autophagy gene Atg5 is essential for T cell survival and proliferation, suggesting that autophagy is a novel mechanism regulating mature T cell homeostasis. However, the underlying molecular mechanisms by which autophagy promotes T lymphocyte survival and proliferation remain unknown. Specifically, it is not clear whether the defect in Atg5-/- T cells is caused by an inability to form autophagosomes or an autophagy-independent function of Atg5? More importantly, if impaired autophagy compromises T cell survival, by what mechanism does autophagy inhibit death in T lymphocytes? Using conditional deletion of a second autophagy gene, Atg7, in T lymphocytes, we have established an essential role for autophagy in the survival of naive T lymphocytes. We have found that mitochondrial homeostasis is disrupted in T cells lacking Atg5 or Atg7. These results suggest that autophagy plays a key role in T cell function through maintaining the homeostasis of intracellular organelles. Our overall hypothesis is that autophagic function in mature primary T lymphocytes is required for cell survival and TCR-mediated proliferation through maintaining turnover of cytoplasmic material, in particular the essential organelle structures such as mitochondria. We proposed three specific aims to test this hypothesis.
In aim 1, we will determine how autophagy is regulated in primary T lymphocytes and the developmental stages at which the induction of autophagy contributes to cell survival.
In aim 2, we will examine how deregulation of organelle homeostasis contributes to cell death in autophagy-deficient primary T lymphocytes.
In aim 3, we will establish the mechanisms by which loss of autophagy genes inhibits cell cycle progression during T cell proliferation. Results from this study will shed important insights to the molecular mechanisms by which mature T cell function is regulated. Better understanding this process will undoubtedly help future design of strategies boosting T cell immune responses to pathogens.
We propose to study the roles of an essential intracellular process termed autophagy in regulating T lymphocyte survival and proliferation. The results from this study, if funded, will provide important information for the treatment and prevention of diseases related to T lymphocytes including designing vaccines to boost T cell immune response to microbial pathogens, tumor genesis and autoimmune disease development.
|Wang, Yu; Sun, Sheng-Nan; Liu, Qing et al. (2016) Autocrine Complement Inhibits IL10-Dependent T-cell-Mediated Antitumor Immunity to Promote Tumor Progression. Cancer Discov 6:1022-35|
|Jia, Wei; He, Ming-Xiao; McLeod, Ian X et al. (2015) Autophagy regulates T lymphocyte proliferation through selective degradation of the cell-cycle inhibitor CDKN1B/p27Kip1. Autophagy 11:2335-45|
|He, Ming-Xiao; He, You-Wen (2015) c-FLIP protects T lymphocytes from apoptosis in the intrinsic pathway. J Immunol 194:3444-51|
|He, Ming-Xiao; He, You-Wen (2013) CFLAR/c-FLIPL: a star in the autophagy, apoptosis and necroptosis alliance. Autophagy 9:791-3|
|Dunkle, Alexis; Dzhagalov, Ivan; Gordy, Claire et al. (2013) Transfer of CD8+ T cell memory using Bcl-2 as a marker. J Immunol 190:940-7|
|He, M-X; He, Y-W (2013) A role for c-FLIP(L) in the regulation of apoptosis, autophagy, and necroptosis in T lymphocytes. Cell Death Differ 20:188-97|
|He, Ming-Xiao; He, You-Wen (2012) Suppressing autoimmunity by TGF-Î²: not just through T(reg) cells. Cell Mol Immunol 9:371-2|
|Wang, Yihua; Wang, Xiao Dan; Lapi, Eleonora et al. (2012) Autophagic activity dictates the cellular response to oncogenic RAS. Proc Natl Acad Sci U S A 109:13325-30|
|McLeod, Ian X; He, You-Wen (2012) Editorial: TRPV1: how thymocytes sense stress and respond with autophagy. J Leukoc Biol 92:409-11|
|McLeod, Ian X; Jia, Wei; He, You-Wen (2012) The contribution of autophagy to lymphocyte survival and homeostasis. Immunol Rev 249:195-204|
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