Novel PTPRD interaction Controlling T cell Responsiveness

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 DESCRIPTION (provided by applicant): T cell responsiveness relies on the balance of signals from co-stimulatory and co-inhibitory interactions that control various activities directly in T cels or indirectly in APC. Interestingly, there are a number of molecules that have both stimulatory and inhibitory activity as they can interact with more than one partner, typified by CD86 binding both CD28 and CTLA-4, and HVEM binding LIGHT and BTLA. These interactions then have potential relevance in multiple immune diseases including autoimmunity and cancer. 4-1BB (CD137, TNFRSF9), a member of the tumor-necrosis factor receptor (TNFR) super-family, was originally identified as an inducible co-stimulatory molecule on activated T cells that promotes clonal expansion and survival in effector T cells when it interacts with its recognized TNF family ligand (4-1BBL, TNFSF9). In contrast we have found an early inhibitory role for 4-1BB that does not rely on interaction with 4-1BBL, such that the absence of 4-1BB on naïve T cells leads to enhanced expansion and differentiation. Furthermore, 4-1BB-deficient mice spontaneously develop an autoimmune-type phenotype with inflammation at the mucosal interfaces. We have now found that 4-1BB can bind to protein tyrosine phosphatase (PTP) receptor delta (PTPRD), a putative inhibitory molecule that is expressed on B cells and dendritic cells. Since the identification of CD45 as a membrane-expressed receptor that has PTP activity, a number of other membrane-bound PTP receptors have been described. However, their significance to T cell immunity has not been appreciated. We hypothesize that ligation of PTPRD suppresses maturation and activation of APC and limits the ability of APC to promote strong T cell priming. The studies in this grant will investigate the nature of the interaction of 4-1BB with PTPRD and determine with PTPRD-deficient mice and APC how PTPRD contributes to regulating the generation of T cell immunity. We hypothesize that PTPRD will be a new example of a checkpoint inhibitor of relevance to autoimmunity and cancer.