Immune responses must be regulated to ensure effective pathogen elimination and self tolerance. ICOS andPD-L1 play key roles in regulating this critical balance between T cell activation and tolerance. During thecurrent funding period, we have been investigating how ICOS and PD-L1 in regulate pathogenic vs.protective T cell responses. Our studies point to novel roles for both ICOS and PD-L1 In sustaining thefunction of regulatory T cell cells and maintaining T cell tolerance. We have found that ICOS does not controlthe induction of regulatory CD4 T cells during mucosal tolerance, but instead, appears necessary forsustaining CD4 regulatory cells during mucosal tolerance. ICOS, c-Maf and IL-21 coordinately act topromote differentiation of IL-10 producing regulatory type 1 (Tr1) cells, but ICOS appears to be crucial formaintaining IL-27 driven, IL-10 producing Tri cells. These findings lead us to hypothesize that ICOS, c-mafand lL-27 wori< in concert to regulate mucosal tolerance. Likewise, we have identified mechanisms by whichPD-L1 controls tolerance: PD-L1 limits activation of self-reactive T cells, function of self-reactive effector cellsand promotes induction and maintenance of adaptive regulatory T cells. PD-L1 on non-hematopoietic cellspromotes tissue tolerance. PD-L1 and PD-1 have become new therapeutic targets in cancer and chronicinfection, since blockade of PD-1 or PD-L1 can activate anti-viral or anti tumor immunity. In view of their keyroles In regulating tolerance, further studies are needed to determine how to effectively minimize the risk ofimmune-mediated tissue damage and autoimmunity, while modulating PD-L1 and PD-1 to enhance virus ortumor control. Our discovery of the PD-L1 :B7-1 pathway leads us to ask whether PD-L1 :PD-1 and PD-L1:B7-1 interactions have unique or overiapping roles in T cell tolerance, and investigate the function of PD-L1 on T cells during tolerance. We hypothesize that PD-L1:B7-1, as well as PD-L1:PD-1 interactions, inhibitself-reactive T cell responses, and that PD-L1 has a T cell intrinsic role in controlling T cell responses. Totest these hypotheses, our Specific Aims are to: 1) Investigate the inter-relationships among ICOS, IL-27 andc-maf during mucosal tolerance; 2) Analyze the functional significance of the novel PD-L1:B7-1 pathway andrelative contributions of PD-L1:B7-1 and PD-L1 interactions in regulating T cell tolerance and autoimmunity;3) Investigate the role of PD-L 1 onT cells in regulating T cell tolerance; and 4) Dissect the roles of PD-L 1 onspecific cell types in mucosal tolerance. These studies should complement each other to further ourunderstanding of mechanisms that control tolerance and autoimmunity, and provide therapeutic insights.

Public Health Relevance

These studies will provide new insights into how ICOS and PD-L1 regulate the balance between T cellactivation and tolerance. The results of our studies will have implications for developing new therapies forhuman chronic viral infections, cancer, autoimmune diseases and increasing success of transplantation. Ourfindings may assist with approaches for controlling Treg plasticity and help determine how to tiest manipulatePD-L1 therapeutically to enhance pathogen or tumor control, and minimize autoimmunity/immunopathology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37AI038310-17
Application #
7914841
Study Section
Special Emphasis Panel (NSS)
Program Officer
Lapham, Cheryl K
Project Start
1995-07-15
Project End
2015-12-31
Budget Start
2011-01-01
Budget End
2011-12-31
Support Year
17
Fiscal Year
2011
Total Cost
$421,665
Indirect Cost
Name
Harvard University
Department
Pathology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Saha, Asim; O'Connor, Roddy S; Thangavelu, Govindarajan et al. (2016) Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality. J Clin Invest 126:2642-60
Sage, Peter T; Ron-Harel, Noga; Juneja, Vikram R et al. (2016) Suppression by TFR cells leads to durable and selective inhibition of B cell effector function. Nat Immunol 17:1436-1446
Godec, Jernej; Cowley, Glenn S; Barnitz, R Anthony et al. (2015) Inducible RNAi in vivo reveals that the transcription factor BATF is required to initiate but not maintain CD8+ T-cell effector differentiation. Proc Natl Acad Sci U S A 112:512-7
Sage, Peter T; Sharpe, Arlene H (2015) In vitro assay to sensitively measure T(FR) suppressive capacity and T(FH) stimulation of B cell responses. Methods Mol Biol 1291:151-60
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
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; Sharpe, Arlene H (2015) T follicular regulatory cells in the regulation of B cell responses. Trends Immunol 36:410-8
Sage, Peter T; Alvarez, David; Godec, Jernej et al. (2014) Circulating T follicular regulatory and helper cells have memory-like properties. J Clin Invest 124:5191-204
Sage, Peter T; Paterson, Alison M; Lovitch, Scott B et al. (2014) The coinhibitory receptor CTLA-4 controls B cell responses by modulating T follicular helper, T follicular regulatory, and T regulatory cells. Immunity 41:1026-39
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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