CD4 T cell autophagy is integral to memory maintenance

Abstract

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 f/f 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.