This revised PPG competing renewal application is driven by the fundamental and therapeutic importance of costimulatory pathways for regulating T cell activation and tolerance, and builds upon our significant progress since initial awarding of this PPG in 2003. The synergy in our PPG is highlighted by 111 publications, 49 of which have been co-authored by multiple PPG investigators, and include 33 new publications since the first (May 2007) submission. Our PPG also has had a significant role in mentoring fellows who work on joint projects, and fostering development of junior faculty. Our PPG has not only provided novel insights to the field, but allowed sharing of novel mAbs and fusion proteins, and mouse strains with the broader scientific community that resulted in better understanding of the functions of costimulatory pathways above and beyond our PPG aims. The overall objective of our PPG is to achieve a mechanistic understanding of the roles of pathways in the B7:CD28 family in regulating T cell activation and tolerance. Building upon our published and preliminary data, these goals include: 1) investigate roles of these pathways in regulating T cell responses in target tissues versus lymphoid organs, 2) dissect functional hierarchy, dominance and redundancy among these pathways, and 3) study how these pathways regulate the balance between protective and pathogenic T cell responses, ultimately determining the fate of the immune response, using experimental models of transplantation, autoimmunity, and infection. The proposed PPG renewal application will provide a means by which PPG investigators can continue to work together to address these important issues and develop a comprehensive understanding of the functions of B7:CD28 family members, ultimately leading to development of novel immunotherapeutic strategies. This PPG will facilitate communication among PPG investigators and sharing of a rich collection of tools, transgenic/knockout mice and mAbs and Ig fusion proteins, to address these issues. The use of the same standardized reagents and experimental animals makes it possible to compare and contrast results in different microenvironments and disease models. There will be 3 Projects (Transplantation, Autoimmunity, Infection) and 3 Cores (Administrative, Antibody/lg fusion protein, Transgenic/Knockout). The "Administrative Core" will be responsible for providing scientific direction and coordination, fiscal oversight and administrative support for the PPG. Overall, this PPG should provide fundamental knowledge for therapeutic manipulation of these important regulatory pathways.

Public Health Relevance

}: These studies will provide the basis for understanding how, where and when costimulatory molecules regulate allograft rejection, organ-specific autoimmune diseases, and chronic viral infection 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-RJ-I (J1))
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Lapham, Cheryl K
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Harvard University
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Flynn, Ryan; Du, Jing; Veenstra, Rachelle G et al. (2014) Increased T follicular helper cells and germinal center B cells are required for cGVHD and bronchiolitis obliterans. Blood 123:3988-98
Penaloza-MacMaster, Pablo; Kamphorst, Alice O; Wieland, Andreas et al. (2014) Interplay between regulatory T cells and PD-1 in modulating T cell exhaustion and viral control during chronic LCMV infection. J Exp Med 211:1905-18
Sawitzki, Birgit; Brunstein, Claudio; Meisel, Christian et al. (2014) Prevention of graft-versus-host disease by adoptive T regulatory therapy is associated with active repression of peripheral blood Toll-like receptor 5 mRNA expression. Biol Blood Marrow Transplant 20:173-82
Dubovsky, Jason A; Flynn, Ryan; Du, Jing et al. (2014) Ibrutinib treatment ameliorates murine chronic graft-versus-host disease. J Clin Invest 124:4867-76
Xiao, Yanping; Yu, Sanhong; Zhu, Baogong et al. (2014) RGMb is a novel binding partner for PD-L2 and its engagement with PD-L2 promotes respiratory tolerance. J Exp Med 211:943-59
Porichis, Filippos; Hart, Meghan G; Zupkosky, Jennifer et al. (2014) Differential impact of PD-1 and/or interleukin-10 blockade on HIV-1-specific CD4 T cell and antigen-presenting cell functions. J Virol 88:2508-18
Mott, Kevin R; Allen, Sariah J; Zandian, Mandana et al. (2014) Inclusion of CD80 in HSV targets the recombinant virus to PD-L1 on DCs and allows productive infection and robust immune responses. PLoS One 9:e87617
Joller, Nicole; Lozano, Ester; Burkett, Patrick R et al. (2014) Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses. Immunity 40:569-81
Alexander, Kylie A; Flynn, Ryan; Lineburg, Katie E et al. (2014) CSF-1-dependant donor-derived macrophages mediate chronic graft-versus-host disease. J Clin Invest 124:4266-80
Ding, Zhi-Chun; Lu, Xiaoyun; Yu, Miao et al. (2014) Immunosuppressive myeloid cells induced by chemotherapy attenuate antitumor CD4+ T-cell responses through the PD-1-PD-L1 axis. Cancer Res 74:3441-53

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