Immune responses must be regulated to ensure effective pathogen elimination and self tolerance. ICOS and PD-L1 play key roles in regulating this critical balance between T cell activation and tolerance. During the current 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 the function of regulatory T cell cells and maintaining T cell tolerance. We have found that ICOS does not control the induction of regulatory CD4 T cells during mucosal tolerance, but instead, appears necessary for sustaining CD4 regulatory cells during mucosal tolerance. ICOS, c-Maf and IL-21 coordinately act to promote differentiation of IL-10 producing regulatory type 1 (Tr1) cells, but ICOS appears to be crucial for maintaining IL-27 driven, IL-10 producing Tri cells. These findings lead us to hypothesize that ICOS, c-maf and lL-27 wori

Public Health Relevance

These studies will provide new insights into how ICOS and PD-L1 regulate the balance between T cell activation and tolerance. The results of our studies will have implications for developing new therapies for human chronic viral infections, cancer, autoimmune diseases and increasing success of transplantation. Our findings may assist with approaches for controlling Treg plasticity and help determine how to tiest manipulate PD-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 #
5R37AI038310-18
Application #
8208983
Study Section
Special Emphasis Panel (NSS)
Program Officer
Lapham, Cheryl K
Project Start
1995-07-15
Project End
2015-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
18
Fiscal Year
2012
Total Cost
$421,665
Indirect Cost
$171,665
Name
Harvard University
Department
Pathology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
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
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; 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
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
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; 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; 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; 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
Hirahara, Kiyoshi; Ghoreschi, Kamran; Yang, Xiang-Ping et al. (2012) Interleukin-27 priming of T cells controls IL-17 production in trans via induction of the ligand PD-L1. Immunity 36:1017-30
Paterson, Alison M; Brown, Keturah E; Keir, Mary E et al. (2011) The programmed death-1 ligand 1:B7-1 pathway restrains diabetogenic effector T cells in vivo. J Immunol 187:1097-105

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