The investigator will test the hypothesis that CTLA-4 downregulates T-cell activation and is normally involved in the prevention of autoimmunity. Evidence for this premise comes from the investigator's finding that the CTLA-4-deficient mice develop splenomegaly and lymphadenopathy, multi-organ lymphocytic infiltration and tissue destruction with severe myocarditis and pancreatitis, and die by 3-4 weeks of age.
Three specific aims will be tested. The role of CTLA-4 in regulation of T-cell dependent immune responses will be analyzed by determining how CTLA-4 deficiency affects T-cell responses in vitro and whether CTLA-4 mediates its inhibitory effects solely through interactions with B7-1 and B7-2. The mechanisms of CTLA-4-mediated inhibition will be studied using naive and activated T-cells from CTLA-4-deficient, TCR transgenic mice. Emphasis will be placed on susceptibility to apoptosis and lymphokine production. The contribution of CTLA-4 to systemic autoimmune responses will be addressed by assessment of the pathology of in CTLA-4-deficient mice, determination of whether self-reactive T-cells appear in CTLA-4-deficient mice, and whether the course of EAE in MBP-specific TCR transgenic mice is altered when these mice lack CTLA-4.
| 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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