The role of apoptosis in the development and function of T lymphocytes

Zhang, Nu; Hartig, Heather; Dzhagalov, Ivan; Draper, David E.; He, You Wen

doi:10.1038/sj.cr.7290345

Cited by 136 publications

(118 citation statements)

References 254 publications

(310 reference statements)

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“…Additionally, we have also demonstrated that the autophagy gene Atg5 contributes critically to the homeostatic survival of mouse T lymphocytes in vivo (35). As this autophagy protein also interacts with FADD (Fas-associated death domain protein) and Bcl-x L (44,45), Atg5 may regulate T cell survival through its role in autophagosome formation or through interactions with extrinsic or intrinsic death pathways (46,47). To determine whether the process of autophagy contributes to mature T cell survival, we examined the T cell compartment in a second autophagy-deficient genetic model system.…”

Section: Survival Defect In Atg7-deficient Mature T Cellsmentioning

confidence: 99%

Autophagy Is Essential for Mitochondrial Clearance in Mature T Lymphocytes

Pua

Guo

Komatsu

et al. 2009

The Journal of Immunology

382

442

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Macroautophagy plays an important role in the regulation of cell survival, metabolism, and the lysosomal degradation of cytoplasmic material. In the immune system, autophagy contributes to the clearance of intracellular pathogens, MHCII cross-presentation of endogenous Ags, as well as cell survival. We and others have demonstrated that autophagy occurs in T lymphocytes and contributes to the regulation of their cellular function, including survival and proliferation. Here we show that the essential autophagy gene Atg7 is required in a cell-intrinsic manner for the survival of mature primary T lymphocytes. We also find that mitochondrial content is developmentally regulated in T but not in B cells, with exit from the thymus marking a transition from high mitochondrial content in thymocytes to lower mitochondrial content in mature T cells. Macroautophagy has been proposed to play an important role in the clearance of intracellular organelles, and autophagy-deficient mature T cells fail to reduce their mitochondrial content in vivo. Consistent with alterations in mitochondrial content, autophagy-deficient T cells have increased reactive oxygen species production as well as an imbalance in pro- and antiapoptotic protein expression. With much recent interest in the possibility of autophagy-dependent developmentally programmed clearance of organelles in lens epithelial cells and erythrocytes, our data demonstrate that autophagy may have a physiologically significant role in the clearance of superfluous mitochondria in T lymphocytes as part of normal T cell homeostasis.

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Section: Survival Defect In Atg7-deficient Mature T Cellsmentioning

confidence: 99%

Autophagy Is Essential for Mitochondrial Clearance in Mature T Lymphocytes

Pua

Guo

Komatsu

et al. 2009

The Journal of Immunology

382

442

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“…Through this stringent process collectively known as central tolerance, both non-functional T cells and T cells that recognize self-antigens are eliminated. 4 Developing thymocytes depend on glucose for energy production as well as proliferation. 5 Many studies suggest a key role for glucose and glucose metabolism in shaping the thymocyte apoptotic profile.…”

mentioning

confidence: 99%

Anti-apoptotic effect of hyperglycemia can allow survival of potentially autoreactive T cells

2010

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Thymocyte development is a tightly controlled multi-step process involving selective elimination of self-reactive and nonfunctional T cells by apoptosis. This developmental process depends on signaling by Notch, IL-7 and active glucose metabolism. In this study, we explored the requirement of glucose for thymocyte survival and found that in addition to metabolic regulation, glucose leads to the expression of anti-apoptotic genes. Under hyperglycemic conditions, both mouse and human thymocytes demonstrate enhanced survival. We show that glucose-induced anti-apoptotic genes are dependent on NF-jB p65 because high glucose is unable to attenuate normal ongoing apoptosis of thymocytes isolated from p65 knockout mice. Furthermore, we demonstrate that in vivo hyperglycemia decreases apoptosis of thymocytes allowing for survival of potentially self-reactive thymocytes. These results imply that hyperglycemic conditions could contribute to the development of autoimmunity through dysregulated thymic selection.

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“…In the immune system, apoptosis is required for lymphocyte development and homeostasis. Dysregulation of apoptosis leads to a variety of immune disorders, including immunodeficiency, tumorogenesis, allergies, and autoimmunity (Zhang et al, 2005). Detection of chemicalinduced thymocyte apoptosis in vivo is difficult, however, because of the rapid clearance of apoptotic cells by phagocytes (Savill and Haslett, 1995;Kamath et al, 1997;Pryputniewicz et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, methoxychlor induced prominent increases in several parameters indicative of induced thymocyte apoptosis, including Annexin V-FITC + cells, caspase (3/7, 8, and 9) activities, and DNA fragmentation. This type of dysregulation of apoptosis in the thymus is known to lead to various immune disorders, including immunodeficiency, tumorigenesis, allergies, and autoimmunity (Zhang et al, 2005). Our previous results demonstrated that short-term exposure has the potential to detect the immunosuppression caused by chemicals present in the environment.…”

Section: Research Articlementioning

confidence: 99%