Chaperone mediated autophagy regulates T cell responses through targeted degradation of negative regulators of T cell activation

Chaperone mediated autophagy (CMA) targets soluble proteins for lysosomal degradation. Here we show that CMA is activated in T cells in response to T cell receptor (TCR) engagement, which induces the expression of the lysosomal CMA receptor, LAMP-2A. In activated T cells, CMA targets the ubiquitin ligase Itch and the calcineurin inhibitor Rcan-1 for degradation to maintain activation-induced responses. Consequently, deletion of Lamp2a in T cells causes deficient in vivo responses to immunization or Listeria infection. Impaired CMA activity also occurs in T cells with age, which negatively impacts their function. Restoration of LAMP-2A in aged T cells results in enhancement of activation-induced responses. Our findings define a role for CMA in the regulation of T cell activation through the targeted degradation of negative regulators of T cell activation.