CD4+ T cell activation is dependent on a novel form of ULK1/2-independent autophagy
Autophagy is essential for CD4+ T cell activation and immune regulation. However, during activation both autophagy and anabolic signaling must be simultaneously sustained, challenging established models of pathway antagonism. Here, we show that T cell receptor signaling and co-stimulation induce a non-canonical form of autophagy required for proliferation and cytokine production. Pharmacological and genetic analyses reveal that this pathway is activated concurrently with mTORC1, and is dependent on PIK3C3, but occurs independently of the canonical regulators ULK1/2, AMPK, ATG13, and Beclin 1. Furthermore, immuno-electron microscopy demonstrates that activation generates smaller autophagic structures that associate with multivesicular bodies and exhibit a unique morphology. These findings uncover a fundamental rewiring of autophagy control in CD4+ T cells and identify a novel form of mechanistically and morphologically distinct non-canonical autophagy.