It has been known for more than a decade that T cells require two types of signals for activation, proliferation, and differentiation to effector function: antigen specific signals via the TCR, and additional costimulatory signals provided by specialized APC. The prototypical costimulatory pathway is that mediated by CD28 on the T cell surface with B7-1 or B7-2 on the APC. T cell activation results in expression of CTLA-4, a close homolog of CD28 which binds the same ligands but provides critical downregulatory signals. CD28 and CTLA-4 have a yin/yang relationship and together play a critical role in regulating fairly early stages of T cell responses in lymphoid organs. This pathway offers powerful targets for immune intervention, and can be manipulated to either inhibit unwanted immune responses (eg. autoimmunity, allergy, transplant rejection) or enhance desired responses (eg. Tumor Immunotherapy). Recent years have seen the identification of new costimulatory pathways, including B7h/ICOS, PD-L1, 2/PD-1 and B7-H3/?. Our knowledge of these new pathways is at an early stage, but it seems clear that they have functions which may be partially overlapping but are quite distinct. We and others have recently identified a novel member of the extended B7 family, B7x (also known as B7H4 and B7S1). B7x is widely expressed in lymphoid and non-lymphoid tissues and tumors, and inhibits T cell responses, perhaps by binding to BTLA, a recently identified molecule expressed on activated T cells. We propose that B7x may represent a novel inhibitory pathway that serves to attenuate or prevent tissue-specific autoimmunity, perhaps at the level of effector function, and that if may provide tumors with a means for evasion of anti-tumor responses. The overall goal of this project is to gain more precise and extensive knowledge of the role of B7x in regulating T cell responses and the potential of this novel pathway in therapeutic intervention. Specifically, we propose to: 1) Examine the expression of B7x in lymphoid and non-lymphoid tissues. 2) Determine the functional activity of B7x in a variety of in vitro systems in order to determine the stage of T cell activation at which it acts and the consequences of its engagement on proliferation and survival, cytokine production, cytolysis, and differentiation, and to determine whether it differentially affects T cells activated by different signal strengths. 3) Determine the role of B7x in regulating immune responses in vivo. 4) Identify and characterize T cell receptor(s) for B7x.
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