Function of src-like adaptor proteins in lymphocytes

描述（由申请人提供）：多样的T淋巴细胞和B淋巴细胞使我们能够对各种环境病原体作出反应。对抗原有反应的淋巴细胞可以分化为活化的效应器，变得无反应（无能）或经历活化诱导的细胞死亡。在免疫应答过程中，通过抗原受体的信号强度的改变可能会破坏耐受和免疫之间的平衡。通过t细胞（TCR）或b细胞（BCR）抗原受体的信号传导强度决定了淋巴细胞的命运。抗原受体的内在亲和力和表面密度都决定了它对抗原的亲和力。这种贪婪调节着细胞内信号的强度。最近，细胞内的src-like adaptor protein （SLAP）家族被发现，由两个成员SLAP-1和SLAP-2组成。这些接头是淋巴细胞信号传导的负调节因子，我假设它们通过两种方式调节抗原受体信号传导的阈值：1)SLAP家族成员控制淋巴细胞表面抗原受体的水平；2)它们通过与E3泛素连接酶（如c-Cbl）的相互作用调节抗原受体信号级联成分的半衰期。SLAP接子家族的破坏应导致持续的细胞内信号传导和自身免疫。本提案的目标是：1)定义SLAP-2抑制TCR信号传导的机制；2)阐明SLAP-2功能缺失对抗原受体信号传导和淋巴细胞发育的影响；3)描述SLAP-1和SLAP-2缺乏对淋巴细胞发育和活化的影响。

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.