Identification of Atg5-dependent transcriptional changes and increases in mitochondrial mass in Atg5-deficient T...

Autophagy is implicated in many functions of mammalian cells such as organelle recycling, survival and differentiation, and is essential for the maintenance of T and B lymphocytes. Here, we demonstrate that autophagy is a constitutive process during T cell development. Deletion of the essential autophagy genes Atg5 or Atg7 in T cells resulted in decreased thymocyte and peripheral T cell numbers, and Atg5-deficient T cells had a decrease in cell survival. We employed functional-genetic and integrative computational analyses to elucidate specific functions of the autophagic process in developing T-lineage lymphocytes. Our whole-genome transcriptional profiling identified a set of 699 genes differentially expressed in Atg5-deficient and Atg5-sufficient thymocytes (Atg5-dependent gene set). Strikingly, the Atg5-dependent gene set was dramatically enriched in genes encoding proteins associated with the mitochondrion. In support of a role for autophagy in mitochondrial maintenance in T lineage cells, the deletion of Atg5 led to increased mitochondrial mass in peripheral T cells. We also observed a correlation between mitochondrial mass and Annexin-V staining in peripheral T cells. We propose that autophagy is critical for mitochondrial maintenance and T cell survival. We speculate that, similar to its role in yeast or mammalian liver cells, autophagy is required in T cells for the removal of damaged or aging mitochondria and that this contributes to the cell death of autophagy-deficient T cells.