The PD-1: PD-L1 pathway plays multifaceted roles in controlling the balance between pathogenic and protective immune responses in T cell tolerance and autoimmunity. During the current funding period, our studies have revealed critical roles for the PD-1: PD-L1 pathway in regulating T cell activation, tolerance and immune-mediated tissue damage. We have found that PD-L1 not only inhibits the activation and function of pathogenic effector T cells, but also promotes the development and sustains the function of induced regulatory T cells. In addition, we have identified a novel role for PD-L1 on non-hematopoietic cells in protecting target organs from immune-mediated tissue injury. However, we lack a mechanistic understanding of the function of PD-L1 on different cell types. The great interest in PD-L1 and PD-1 as therapeutic targets gives impetus to further investigation of how these important immunoregulatory molecules regulate autoreactive T cells. The overall goal of this project is to elucidate mechanisms by which PD-L1 controls T cell tolerance, prevents autoimmunity, and limits immune-mediated inflammation locally within tissues. Our published and preliminary data lead us to hypothesize that PD-L1 on specific types of hematopoietic and non-hematopoietic cells will regulate T cell activation, tolerance and autoimmunity-related pathology by distinct mechanisms. We will use our newly generated PD-L1 conditional knockout mice crossed to cell type-specific Cre lines to test this hypothesis in the following Specific Aims Aim 1: To test the hypothesis that there are distinct roles for PD-L1 on specific hematopoietic or non-hematopoietic cell types in regulating the activation, differentiation, and function of potentially pathogenic self-reactive T cells. We will analyze the relative functions of PD-L1 on specific hematopoietic and non-hematopoietic cell types in controlling the activation and differentiation of na?ve myelin-reactive CD4 T cells and the functions of differentiated myelin-reactive effector cells using the myelin oligodendrocyte (MOG) model of experimental autoimmune encephalomyelitis (EAE). 2) To test the hypothesis that there are distinct roles for PD-L1 on specific cell types in controlling the generation and function of regulatory T cells. We will analyze the relative functions of PD-L1 in controlling natural regulatory T cells (nTreg) and induced regulatory T cells (iTreg). We will use the MOG-induced EAE model to study how PD-L1 regulates nTreg expansion, function and plasticity. We will study how PD-L1 on specific cell types promotes iTreg generation, function, and plasticity using a colitis model, where iTreg are best defined. These studies should further our understanding of mechanisms that control tolerance and autoimmunity, and provide insight into how to modulate PD-L1 and PD-1 therapeutically to control autoimmune diseases, chronic infections and cancer.
These studies will provide fundamental information about how, where and when PD-L1 regulates tolerance, autoimmunity and immunopathology. The results of our studies will have implications for developing new therapies for human malignancies, chronic infections, and autoimmune diseases, and increasing success of transplantation.
| LaFleur, Martin W; Muroyama, Yuki; Drake, Charles G et al. (2018) Inhibitors of the PD-1 Pathway in Tumor Therapy. J Immunol 200:375-383 |
| Sharpe, Arlene H (2017) Introduction to checkpoint inhibitors and cancer immunotherapy. Immunol Rev 276:5-8 |
| Zhang, Ruan; Sage, Peter T; Finn, Kelsey et al. (2017) B Cells Drive Autoimmunity in Mice with CD28-Deficient Regulatory T Cells. J Immunol 199:3972-3980 |
| Juneja, Vikram R; McGuire, Kathleen A; Manguso, Robert T et al. (2017) PD-L1 on tumor cells is sufficient for immune evasion in immunogenic tumors and inhibits CD8 T cell cytotoxicity. J Exp Med 214:895-904 |
| Schildberg, Frank A; Klein, Sarah R; Freeman, Gordon J et al. (2016) Coinhibitory Pathways in the B7-CD28 Ligand-Receptor Family. Immunity 44:955-72 |
| Sage, Peter T; Ron-Harel, Noga; Juneja, Vikram R et al. (2016) Suppression by TFRcells leads to durable and selective inhibition of B cell effector function. Nat Immunol 17:1436-1446 |
| Paterson, Alison M; Lovitch, Scott B; Sage, Peter T et al. (2015) Deletion of CTLA-4 on regulatory T cells during adulthood leads to resistance to autoimmunity. J Exp Med 212:1603-21 |
| Sage, Peter T; Tan, Catherine L; Freeman, Gordon J et al. (2015) Defective TFH Cell Function and Increased TFR Cells Contribute to Defective Antibody Production in Aging. Cell Rep 12:163-71 |
| Schildberg, Frank A; Sharpe, Arlene H; Turley, Shannon J (2015) Hepatic immune regulation by stromal cells. Curr Opin Immunol 32:1-6 |
| Sage, Peter T; Francisco, Loise M; Carman, Christopher V et al. (2013) The receptor PD-1 controls follicular regulatory T cells in the lymph nodes and blood. Nat Immunol 14:152-61 |
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