Function of src-like adaptor proteins in lymphocytes

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DESCRIPTION (provided by applicant): A diverse repertoire of T and B lymphocytes enables us to respond to a wide variety of environmental pathogens. Lymphocytes in response to antigen can differentiate into activated effectors, become non-responsive (anergic) or undergo activation-induced cell death. Alterations in the strength of signaling through the antigen receptor may disrupt the balance between tolerance and immunity during an immune response. Strength of signaling via the T-cell (TCR) or B-cell (BCR) antigen receptors determines the fate of that lymphocyte. Both the intrinsic affinity and surface density of the antigen receptor contribute to its avidity for antigen. This avidity regulates strength of signaling within the cell. Recently, the src-like adaptor protein (SLAP) family of intracellular adaptors, comprised of two members SLAP-1 and SLAP-2, has been identified. These adaptors are negative regulators of lymphocyte signaling and I hypothesize that they modulate the threshold of antigen receptor signaling in two ways: 1) SLAP family members control the level of surface antigen receptor on a lymphocyte; and 2) they regulate the half-life of components of the antigen receptor signaling cascade through their interactions with E3 ubiquitin ligases, such as c-Cbl. Disruption of the SLAP family of adaptors should lead to sustained intracellular signaling and autoimmunity. The goal of this proposal is to: 1) define mechanisms by which SLAP-2 inhibits TCR signaling; 2) elucidate effects of loss of SLAP-2 function on antigen receptor signaling and lymphocyte development; 3) characterize the effects of SLAP-1 and SLAP-2 deficiency on lymphocyte development and activation.