A critical role for the autophagy gene Atg5 in T cell survival and proliferation

By H. Pua, I. Dzhagalov, Mariana I. Chuck, N. Mizushima, You-Wen He. Journal of Experimental Medicine, 2007

642 citations recorded by the source corpus.

Macroautophagy (hereafter referred to as autophagy) is a well-conserved intracellular degradation process. Recent studies examining cells lacking the autophagy genes Atg5 and Atg7 have demonstrated that autophagy plays essential roles in cell survival during starvation, in innate cell clearance of microbial pathogens, and in neural cell maintenance. However, the role of autophagy in T lymphocyte development and survival is not known. Here, we demonstrate that autophagosomes form in primary mouse T lymphocytes. By generating Atg5−/− chimeric mice, we found that Atg5-deficient T lymphocytes underwent full maturation. However, the numbers of total thymocytes and peripheral T and B lymphocytes were reduced in Atg5 chimeras. In the periphery, Atg5−/− CD8+ T lymphocytes displayed dramatically increased cell death. Furthermore, Atg5−/− CD4+ and CD8+ T cells failed to undergo efficient proliferation after TCR stimulation. These results demonstrate a critical role for Atg5 in multiple aspects of lymphocyte development and function and suggest that autophagy may be essential for both T lymphocyte survival and proliferation.

Subfields: Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/330a8ec7e2659fe222b2fae559179e78c86c7439

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Citations in the corpus

Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis (2007, background): “In many models of Crohn disease and other inflammatory disorders, T cells are the primary effectors, and autophagy is a vital process for T cell maintenance and homeostasis, as demonstrated by the increased cell death seen in Atg5 −/− T cells and their inability to proliferate after stimulatio”
Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013, background): “Proper induction of autophagy has been shown to be important for the maintenance of cellular bioenergetics and sustained T cell viability after activation (25, 26).”
The autophagy protein Atg7 is essential for hematopoietic stem cell maintenance (2011, neutral): “Stably reconstituted autophagy-deficient FL chimeras have been achieved in two previous studies (Pua et al., 2007; Zhang et al., 2009; reviewed in Mortensen et al., 2010b).”
Guidelines for the use and interpretation of assays for monitoring autophagy (2012, background): “In this respect it is noteworthy that some cell-types of the immune system such as dendritic cells(260) seem to tolerate loss of autophagy fairly well, whereas others such as T and B cells are compromised in their development and function after autophagy inhibition.(757,758) In addition to pharmacol”
Toll‐like receptors control autophagy (2008, background): “Autophagy has a role in T-cell homeostasis (Li et al, 2006), for example by controlling T-cell lifespan once they exit the thymus (Pua et al, 2007), and is an effector of Th1–Th2 polarization in defense against intracellular pathogens (Harris et al, 2007).”
Dying for a cause: NETosis, mechanisms behind an antimicrobial cell death modality (2011, positive): “This reconstitution normalizes neutrophil counts, which suggests that autophagy does not mediate neutrophil survival.(72) Recent data provide evidence for autophagy’s contribution to distinct antimicrobial strategies rather than to neutrophil development or survival.”
Autophagy in mammalian development and differentiation (2010, background): “Atg5 −/− chimaeric mice also show a similar decrease in T and B lymphocyte numbers and defects in stimulation-induced proliferatio”
The dynamic nature of autophagy in cancer. (2011, background): “Indeed, autophagy is important in the proper functioning of multiple immune cell types, including T cells and macrophages (Pua et al. 2007; Deretic 2011; Levine et al. 2011).”
Autophagy suppresses tumor progression by limiting chromosomal instability. (2007, neutral): “2004) and T lymphocyte development (Pua et al. 2006).”
Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (2012, positive): “are compromised in their development and function after autophagy inhibition.(1213,1214) In addition to pharmacological inhibition, RNA silencing, gene knockout and dominant negative RAB and ATG protein expression, pathogen-derived autophagy inhibitors can also be considered to manipulate autophagy.”
Homeostasis of naive and memory T cells. (2008, background): “Hence, T cells lacking Ag5, a crucial autophagy gene, develop normally in the thymus but fail to survive and undergo spontaneous apoptosis after exit to the periphery (Pua et al., 2007).”
Role of autophagy in cancer (2007, background): “Furthermore, ATG5 is required for maintaining T-cell survival and proliferatio”
Self-eating and self-killing: crosstalk between autophagy and apoptosis (2007, background): “T-cell-specific knockout of Atg5 also results in the increased apoptosis of mature T cells in peripheral organs, which correlates with an enhanced susceptibility to cell death induced by stimulation of the T-cell recepto”