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 Atg5f/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.
Highlights
Autophagy is a catabolic process, required to produce energy notably under nutrient deprivation
To resolve the question whether autophagy is required for mature T cell homeostasis, we crossed Atg5f/f animals with mice harbouring a transgene allowing CRE expression, under the control of the distal part of the Lck promoter, only active in mature T cells
We observed a decrease in the proportion and number of spleen CD8+ T cells (Fig. 1C,D) from Atg5f/f distal Lck (dLck)-cre mice compared to controls
Summary
Autophagy is a catabolic process, required to produce energy notably under nutrient deprivation. Three other studies addressed this question in vivo for CD8+ T cells, by transfer experiments and using conditional deletion models only active at the CD8 T cell effector stage They concluded that CD8+ T cells require autophagy for their survival as memory cells[11,12,13]. We generated mice with a deletion of Atg[5], only in mature T cells, using the distal Lck (dLck) promoter conditional knock-out strategy[14] With this new model, we wanted to precisely define the role of autophagy in peripheral T cell homeostasis and function, in the absence of any developmental issue. These observations endow autophagy with a central role in the survival of memory CD4+ T cells
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