Chaperone-mediated autophagy is required for regulatory T cell function.

Chaperone-mediated autophagy (CMA) is a selective form of protein degradation in lysosomes that declines with age. Besides protein quality control, CMA also regulates several cellular processes through timely proteome remodeling. We previously demonstrated the importance of CMA in the activation of helper T cells. In this work, we analyzed the role of CMA in the generation and function of regulatory T cells (Tregs), a specialized type of T cells that suppress immune responses. We found that the basal CMA activity of Tregs further increases upon their activation. Using a Treg-specific CMA-deficient mouse model, we show that CMA is crucial for maintenance of peripheral tolerance by Tregs. Mice with CMA-defective Tregs display signs of chronic inflammation, which results in reduced survival as they age. We demonstrate that CMA-deficient Tregs have reduced suppressive activity in vivo using an experimental model of inflammatory bowel disease and a second model of tumor-induced immune response. Comparative quantitative proteomic analysis enabled us to identify the subproteome degraded by CMA and, consequently, the cellular pathways modulated by this type of autophagy to sustain Treg homeostasis and function. Collectively, our findings uncover a previously unknown role for CMA in regulating Treg function.