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 nave 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.

Public Health Relevance

Co-stimulatory and co-inhibitory interactions between receptor-ligand pairs expressed on T cells and APC or other cells can determine the extent of T cell immunity, and are of relevance for the pathogenesis of autoimmune and inflammatory disease as well as protection against tumor growth. A member of the TNFR superfamily, 4-1BB, that is expressed on T cells can have both stimulatory and inhibitory activity. The binding partner that mediates the inhibitory activity has not been known. We have found that 4-1BB can interact with a novel partner in PTPRD. By understanding the functional importance of this new interaction and the overall role of PTPRD in immunity, we have the potential to gain knowledge that might lead to ways to either enhance or suppress T cell responses, and might be therapeutically relevant in a number of disease settings.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Cellular and Molecular Immunology - A Study Section (CMIA)
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Ramachandra, Lakshmi
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La Jolla Institute
La Jolla
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Mehta, Amit K; Gracias, Donald T; Croft, Michael (2018) TNF activity and T cells. Cytokine 101:14-18
Croft, Michael; Siegel, Richard M (2017) Beyond TNF: TNF superfamily cytokines as targets for the treatment of rheumatic diseases. Nat Rev Rheumatol 13:217-233