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
Schools of Medicine
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Xu, Jie; Sun, Heather H; Fletcher, Christopher D M et al. (2016) Expression of Programmed Cell Death 1 Ligands (PD-L1 and PD-L2) in Histiocytic and Dendritic Cell Disorders. Am J Surg Pathol 40:443-53
Borges, Christopher M; Reichenbach, Dawn K; Kim, Beom Seok et al. (2016) Regulatory T cell expressed MyD88 is critical for prolongation of allograft survival. Transpl Int 29:930-40
Chapuy, Bjoern; Roemer, Margaretha G M; Stewart, Chip et al. (2016) Targetable genetic features of primary testicular and primary central nervous system lymphomas. Blood 127:869-81
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
Schönle, Anne; Hartl, Frederike A; Mentzel, Jan et al. (2016) Caveolin-1 regulates TCR signal strength and regulatory T-cell differentiation into alloreactive T cells. Blood 127:1930-9
Flynn, Ryan; Paz, Katelyn; Du, Jing et al. (2016) Targeted Rho-associated kinase 2 inhibition suppresses murine and human chronic GVHD through a Stat3-dependent mechanism. Blood 127:2144-54
Zeiser, Robert; Blazar, Bruce R (2016) Preclinical models of acute and chronic graft-versus-host disease: how predictive are they for a successful clinical translation? Blood 127:3117-26
Hirakawa, Masahiro; Matos, Tiago; Liu, Hongye et al. (2016) Low-dose IL-2 selectively activates subsets of CD4(+) Tregs and NK cells. JCI Insight 1:e89278
Li, Wei; Liu, Liangyi; Gomez, Aurelie et al. (2016) Proteomics analysis reveals a Th17-prone cell population in presymptomatic graft-versus-host disease. JCI Insight 1:
Lo, Tsun-Ho; Silveira, Pablo A; Fromm, Phillip D et al. (2016) Characterization of the Expression and Function of the C-Type Lectin Receptor CD302 in Mice and Humans Reveals a Role in Dendritic Cell Migration. J Immunol 197:885-98

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