CD4 T cell autophagy is integral to memory maintenance.

Studies of mice deficient for autophagy in T cells since thymic development, concluded that autophagy is integral to mature T cell homeostasis. Basal survival and functional impairments in vivo, limited the use of these models to delineate the role of autophagy during the immune response. We generated Atg5 distal Lck (dLck)-cre mice, with deletion of autophagy only at a mature stage. In this model, autophagy deficiency impacts CD8 T cell survival but has no influence on CD4 T cell number and short-term activation. Moreover, autophagy in T cells is dispensable during early humoral response but critical for long-term antibody production. Autophagy in CD4 T cells is required to transfer humoral memory as shown by injection of antigen-experienced cells in naive mice. We also observed a selection of autophagy-competent cells in the CD4 T cell memory compartment. We performed in vitro differentiation of memory CD4 T cells, to better characterize autophagy-deficient memory cells. We identified mitochondrial and lipid load defects in differentiated memory CD4 T cells, together with a compromised survival, without any collapse of energy production. We then propose that memory CD4 T cells rely on autophagy for their survival to regulate toxic effects of mitochondrial activity and lipid overload.