Atg5 Is Essential for the Development and Survival of Innate Lymphocytes

Autophagy is an essential cellular survival mechanism that is required for adaptive lymphocyte development; however, its role in innate lymphoid cell (ILC) development remains unknown. Furthermore, the conditions that promote lymphocyte autophagy during homeostasis are poorly understood. Here, we demonstrate that Atg5, an essential component of the autophagy machinery, is required for the development of mature natural killer (NK) cells and group 1, 2, and 3 innate ILCs. Although inducible ablation of Atg5 was dispensable for the homeostasis of lymphocyte precursors and mature lymphocytes in lymphoreplete mice, we found that autophagy is induced in both adaptive and innate lymphocytes during homeostatic proliferation in lymphopenic hosts to promote their survival by limiting cell-intrinsic apoptosis. Induction of autophagy through metformin treatment following homeostatic proliferation increased lymphocyte numbers through an Atg5-dependent mechanism. These findings highlight the essential role for autophagy in ILC development and lymphocyte survival during lymphopenia. [Display omitted] •Atg5 is required for innate lymphocyte development•Adaptive and innate lymphocytes induce autophagy during homeostatic expansion•Autophagy is essential for lymphocyte survival during lymphopenia•Metformin increases autophagy to enhance lymphocyte survival in lymphopenic hosts Autophagy is an essential cellular survival mechanism induced during periods of stress. O’Sullivan et al. demonstrate that the essential autophagy gene Atg5 is required for the development and survival of all ILC lineages by limiting cell-intrinsic apoptosis.