Mechanisms of T cell inhibitory pathways

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DESCRIPTION (provided by applicant): The main goal of this K08 Award is to study a new T cell inhibitory pathway in the B7:CD28 family of costimulatory molecules that regulates T cell activation and tolerance. The PI will be mentored at Harvard Medical School by Dr. Arlene Sharpe, an expert in the area of T cell costimulation. We have found that Programmed Death-1 Ligand 1 (PD-L1) on T cells can interact with B7-1, and that this interaction can inhibit T cell responses. We will test the hypothesis that PD-L1 on T cells plays an important role in controlling T cell activation, effector responses, and autoimmunity. We have a number of unique tools, including gene-deficient mice and PD-L1 antibodies that enable us to dissect the molecular mechanisms of PD-L1 signaling on T cells and investigate its roles in controlling in vivo responses. Our specific aims are: 1. Establish the mechanisms by which PD-L1 on T cells exerts inhibitory effects in mice and humans. In this Aim, we will test whether PD-L1 on T cells exerts an inhibitory effect by 1) modifying TCR signaling pathways, and/or by 2) utilizing a signaling partner or second chain to enact inhibitory effects. We will also test if ligation of PD-L1 on human T cells is inhibitory. These subaims will provide insight into the mechanisms by which PD-L1 on T cells inhibits responses and the potential for therapeutic manipulation of PD-L1 on human T cells. 2. Determine the roles of PD-L1 on T cells and its partners at the immunological synapse (IS). T cells are activated and regulated by contact with APCs at the IS. B7-1 on APCs can interact with CD28, CTLA-4, or PD-L1 on the T cell, raising the question: how does PD-L1 compete with CD28 and CTLA-4 for B7-1 interactions? We will focus on how PD-L1 on T cells competes with CD28 for binding to B7-1 in the early synapse (microclusters) and the late synapse (T cell-DC synapse). These studies will complement those in Aim 1 to investigate another means by which PD-L1 on T cells may exert its inhibitory effects. 3. Characterize in vivo effects of PD-L1 on T cells: activation and autoimmunity. I will examine the in vivo role of PD-L1 on CD4 and CD8 T cells during activation and effector responses. This aim will test the hypothesis that the PD-L1 pathway may control self-reactive T cells during autoimmune responses in vivo, using an autoimmune model of diabetes. In this proposal, I plan to acquire new skills in areas of T cell biology, including microscopy and in vivo studies of autoimmunity. My long-term goal is to combine my background in basic science and clinical medicine to be an academic physician-scientist and independent investigator, examining the fundamental roles of inhibitory T cell pathways as they regulate autoimmunity and infectious diseases. RELEVANCE: Blockade of PD-L1 has become an important therapeutic target. These studies will provide insights into new mechanisms to control T cell responses in microbial immunity, tumor immunity, and autoimmunity, and will provide fundamental insights into mechanisms of inhibition of T cells.