This PPG competing renewal application is driven by the fundamental and therapeutic importance of costimulatory pathways in regulating T cell activation, tolerance, and exhaustion and builds upon our significant progress since initial award of this PPG in 2003. Our productivity is highlighted by 111 primary publications and 22 reviews. Our PPG also has had a significant role in fostering development of junior faculty, and sharing novel mAbs and mouse strains with the broader scientific community, resulting in better understanding of costimulation above and beyond our PPG aims. Our overarching goal is to develop a comprehensive understanding of how positive and negative second signals regulate T cell activation, tolerance and exhaustion. Working together, we have discovered that the PD-1 pathway has multifaceted immunoregulatory functions. To better understand mechanisms of PD-1 signaling in vivo, we generated novel PD-1 signaling domain mutant mice and determined that both the PD-1 ITIM and ITSM motifs mediate PD-1 signaling in vivo. Notably, our data suggest the possibility to dissociate beneficial effects of PD-1 pathway blockade on pathogen/tumor immunity from autoimmunity and immunopathology. We also found that the inhibitory receptors CD101 and CD112R are highly expressed on more terminally exhausted T cells with distinctive functional properties during chronic infection, and on highly suppressive regulatory T cells. These discoveries demonstrate ongoing synergy within our PPG. The sharing of unpublished results and discussion of data have inspired hypotheses and experiments bidirectionally in all projects, which drive the focus of this application. Our major goals are to investigate: 1) Roles of the PD-1 ITSM and ITIM motifs in regulating different T cell subsets in different disease states, 2) How the PD-1 pathway controls pathogenic and protective T cells in tissue-dependent contexts, 3) Roles of CD101 and CD112R in controlling T cell activation, tolerance and exhaustion, and 4) Interactions of CD101 and CD112R with PD-1 in regulating T cell responses, using models of infection, chronic graft versus host disease (cGVHD), cancer and autoimmunity. Our proposed Program will consist of 3 highly integrated and interactive Projects, supported by 3 Cores. Project 1 (Sharpe/Ahmed) will focus on the roles of PD-1, CD101 and CD112R in controlling protective immunity during acute and chronic viral infections. Project 2 (Kuchroo/ Sharpe) will study how PD-1 and CD112R regulate autoimmunity and anti- tumor immunity. Project 3 (Blazar/Sage) will investigate how PD-1, CD101 and CD112R regulate cGVHD. Core A (Sharpe) will provide administrative and scientific coordination. Core B (Freeman) will provide novel mAbs and Ig fusion proteins. Core C (Sharpe) will provide novel mouse strains. The use of the same standardized tools makes it possible to compare and contrast results in different settings and disease models. Mechanistic insights from our proposed studies should guide translation into therapies targeting coinhibitory pathways for human chronic viral infections, cancer, autoimmune diseases and transplantation.

Public Health Relevance

These studies will provide the basis for understanding how, where and when coinhibitory molecules regulate chronic viral infection, tumors, chronic-graft versus-host disease, and organ-specific autoimmunity. These studies have implications for developing novel immunotherapies based on targeting costimulatory pathways for human chronic viral infections, cancer, autoimmune diseases and transplantation.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
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Special Emphasis Panel (ZAI1)
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Jiang, Chao
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Harvard Medical School
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Wu, Chuan; Chen, Zuojia; Xiao, Sheng et al. (2018) SGK1 Governs the Reciprocal Development of Th17 and Regulatory T Cells. Cell Rep 22:653-665
Juchem, Kathryn W; Sacirbegovic, Faruk; Zhang, Cuiling et al. (2018) PD-L1 Prevents the Development of Autoimmune Heart Disease in Graft-versus-Host Disease. J Immunol 200:834-846
Priyadharshini, Bhavana; Loschi, Michael; Newton, Ryan H et al. (2018) Cutting Edge: TGF-? and Phosphatidylinositol 3-Kinase Signals Modulate Distinct Metabolism of Regulatory T Cell Subsets. J Immunol 201:2215-2219
Porichis, Filippos; Hart, Meghan G; Massa, Alexandra et al. (2018) Immune Checkpoint Blockade Restores HIV-Specific CD4 T Cell Help for NK Cells. J Immunol 201:971-981
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
Chaudhri, Apoorvi; Xiao, Yanping; Klee, Alyssa N et al. (2018) PD-L1 Binds to B7-1 Only In Cis on the Same Cell Surface. Cancer Immunol Res 6:921-929
Ahn, Eunseon; Araki, Koichi; Hashimoto, Masao et al. (2018) Role of PD-1 during effector CD8 T cell differentiation. Proc Natl Acad Sci U S A 115:4749-4754
Wu, Yongxia; Schutt, Steven; Paz, Katelyn et al. (2018) MicroRNA-17-92 is required for T-cell and B-cell pathogenicity in chronic graft-versus-host disease in mice. Blood 131:1974-1986
Gartlan, Kate H; Bommiasamy, Hemamalini; Paz, Katelyn et al. (2018) A critical role for donor-derived IL-22 in cutaneous chronic GVHD. Am J Transplant 18:810-820
Hippen, Keli L; Loschi, Michael; Nicholls, Jemma et al. (2018) Effects of MicroRNA on Regulatory T Cells and Implications for Adoptive Cellular Therapy to Ameliorate Graft-versus-Host Disease. Front Immunol 9:57

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