Self-renewing Lymphocyte Division in The Immune Response

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Project Summary/Abstract When a T lymphocyte is engaged in an immune response, it must divide and produce functional daughter cells, often repeatedly. To maintain continued, clonal production of fresh effector T cells requires that some daughter cells self-renew instead of differentiating. Our laboratory identified the activating signals that induce progenitor T cells to undergo irreversible commitment to differentiation. Preservation of self-renewal, however, requires a dampening mechanism to oppose full activation. Among the most critical signals that dampen T cell activation are the inhibitory receptors, which are now key targets of a revolutionary approach to unleash T cell attack against tumors. While blockade of inhibitory receptors offers clinical benefit in some cases, many treated patients do not experience durable anti-tumor immunity. This project addresses a novel and clinically important question that may represent a major barrier for improving the efficacy of inhibitory receptor blockade: Are inhibitory signals an essential part of a regenerative mechanism allowing some T cells to self-renew as their kindred cells undergo differentiation? Using preclinical models of cancer and chronic-active infectious diseases, 3 specific aims will be addressed: (1) Determine if inhibitory receptor blockade impacts the balance of T cell differentiation and self-renewal in vivo, (2) Define the cell biological mechanisms that support T cell self-renewal under in vivo conditions of repetitive, high-level antigen activation and response intensification by inhibitory blockade, and (3) Test whether the efficacy of inhibitory receptor blockade will be improved by addition of agents that promote T cell self-renewal. The results of these studies could offer novel immune response biomarkers, new strategies for vaccination, and novel or repurposed compounds to augment the efficacy of immunotherapy.