T cell activation requires a tight regulation of positive and negative modulators of signaling pathways downstream of the T cell receptor (TCR). Degradation of specific proteins following TCR engagement is an essential regulatory mechanism that ensures efficient T cell responses. Chaperone-mediated autophagy (CMA) is an inducible form of autophagy that selectively degrades soluble cytosolic proteins that present a pentapetide targeting motif. The ability of CMA to selectively degrade proteins makes this type of autophagy a candidate to contribute to the regulation of the levels of specific signaling intermediates in response to different stimuli. We have recently shown that CMA is activated in CD4+ T cells in response to TCR engagement to regulate signaling pathways downstream of the TCR by selectively targeting inhibitors of TCR signaling for degradation in the lysosomes. In this proposal we intend to elucidate the molecular mechanisms that explain how this specific form of autophagy modulates CD4+ T cell function and characterize how CMA regulates adaptive immune responses in vivo. Our overall goal is to define CMA as a novel regulatory mechanism of T cell activation and to determine the possibility of targeting CMA to modulate T cell responses.
We have found a novel regulatory pathway that controls T cell responses and involves the targeted degradation in the lysosomes of inhibitors of signaling downstream of the T cell antigen receptor by chaperone mediated autophagy, a selective form of autophagy that degrades soluble proteins that contain a specific targeting motif. We have found that this process allows T cell to maintain activation in response to antigen. With these studies we intend to define this new regulatory mechanism that controls T cell function, but also determine the possibility of targeting it to modulate T cell responses, setting the basis for the development of new therapeutic interventions aimed at modulating autophagy to control adaptive immune responses.
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