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Collective control of adaptive immunity by T cell co-inhibitory signaling


The ability of T lymphocytes to detect and eliminate cancer and viral infection is restricted by pathological subversion of the co-inhibitory receptor signaling pathways which normally function to restrain the immune response and preserve "self" tolerance. As a result, cancer treatments employing therapeutic antibodies to block the T cell co-inhibitory receptors PD-1 or CTLA4 have seen dramatic clinical success over the past decade. However, despite extensive efforts to improve and predict patient responses to these therapies, additional advances have been slow to materialize and severe autoimmune side effects remain common. To more effectively manipulate the curative potential of adaptive immunity to eliminate cancer and infectious disease, a greater understanding of how T cell co-receptor signaling operates from the level of single cells and molecules to that of the entire system is critical but remains incomplete. To advance understanding of T cell signaling at the molecular and cellular level, an APEX2 peroxidase-based proximity labeling approach is developed and applied to identify novel effectors and substrates of co-inhibitory immune receptors by mass spectrometry. To clarify how CTLA4 coordinates cellular and system level regulation of immune responses, an alternative mechanism is described in which CTLA4 acts in a cell intrinsic manner to regulate availability of the B7 co-stimulatory ligands on the surface of activated T cells. In this model, CTLA4 control of immune homeostasis is achieved in part by directing cis-endocytosis of T cell B7 ligands which are both endogenously expressed and inherently acquired via trogocytosis upon contact with activating APCs. Importantly, these APC-derived innate inflammatory signals targeted by CTLA4 are displayed to other T cells alongside co-acquired peptide antigen during an immune response. A model is presented in which this pathway thereby allows CTLA4 to exert dual cell intrinsic and extrinsic regulatory function to more efficiently operate at the interface between innate and adaptive immunity and between single T cells and the lymphocyte collective.

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