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 work in concert to regulate mucosal tolerance. Likewise, we have identified mechanisms by which PD-L1 controls tolerance: PD-L1 limits activation of self-reactive T cells, function of self-reactive effector cells and promotes induction and maintenance of adaptive regulatory T cells. PD-L1 on non-hematopoietic cells promotes tissue tolerance. PD-L1 and PD-1 have become new therapeutic targets in cancer and chronic infection, since blockade of PD-1 or PD-L1 can activate anti-viral or anti tumor immunity. In view of their key roles In regulating tolerance, further studies are needed to determine how to effectively minimize the risk of immune-mediated tissue damage and autoimmunity, while modulating PD-L1 and PD-1 to enhance virus or tumor 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, inhibit self-reactive T cell responses, and that PD-L1 has a T cell intrinsic role in controlling T cell responses. To test these hypotheses, our Specific Aims are to: 1) Investigate the inter-relationships among ICOS, IL-27 and c-maf during mucosal tolerance;2) Analyze the functional significance of the novel PD-L1:B7-1 pathway and relative 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 on specific cell types in mucosal tolerance. These studies should complement each other to further our understanding 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 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 #
5R37AI038310-19
Application #
8414801
Study Section
Special Emphasis Panel (NSS)
Program Officer
Lapham, Cheryl K
Project Start
1995-07-15
Project End
2015-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
19
Fiscal Year
2013
Total Cost
$396,365
Indirect Cost
$161,365
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

Showing the most recent 10 out of 24 publications