The PD-1:PD-L1 pathway plays multifaceted roles in controlling the balance between pathogenic and protective immune responses in T cell tolerance and autoimmunity. During the current funding period, our studies have revealed critical roles for the PD-1:PD-L1 pathway in regulating T cell activation, tolerance and immune-mediated tissue damage. We have found that PD-L1 not only inhibits the activation and function of pathogenic effector T cells, but also promotes the development and sustains the function of induced regulatory T cells. In addition, we have identified a novel role for PD-L1 on non-hematopoietic cells in protecting target organs from immune-mediated tissue injury. However, we lack a mechanistic understanding of the function of PD-L1 on different cell types. The great interest in PD-L1 and PD-1 as therapeutic targets gives impetus to further investigation of how these important immunoregulatory molecules regulate autoreactive T cells. The overall goal of this project is to elucidate mechanisms by which PD-L1 controls T cell tolerance, prevents autoimmunity, and limits immune-mediated inflammation locally within tissues. Our published and preliminary data lead us to hypothesize that PD-L1 on specific types of hematopoietic and non-hematopoietic cells will regulate T cell activation, tolerance and autoimmunity-related pathology by distinct mechanisms. We will use our newly generated PD-L1 conditional knockout mice crossed to cell type-specific Cre lines to test this hypothesis in the following Specific Aims.
Aim 1 : To test the hypothesis that there are distinct roles for PD-L1 on specific hematopoietic or non-hematopoietic cell types in regulating the activation, differentiation, and function of potentially pathogenic self-reactive T cells. We will analyze the relative functions of PD-L1 on specific hematopoietic and non-hematopoietic cell types in controlling the activation and differentiation of na?ve myelin-reactive CD4 T cells and the functions of differentiated myelin-reactive effector cells using the myelin oligodendrocyte (MOG) model of experimental autoimmune encephalomyelitis (EAE). 2) To test the hypothesis that there are distinct roles for PD-L1 on specific cell types in controlling the generation and function of regulatory T cells. We will analyze the relative functions of PD-L1 in controlling natural regulatory T cells (nTreg) and induced regulatory T cells (iTreg). We will use the MOG-induced EAE model to study how PD-L1 regulates nTreg expansion, function and plasticity. We will study how PD-L1 on specific cell types promotes iTreg generation, function, and plasticity using a colitis model, where iTreg are best defined. These studies should further our understanding of mechanisms that control tolerance and autoimmunity, and provide insight into how to modulate PD-L1 and PD-1 therapeutically to control autoimmune diseases, chronic infections and cancer.

Public Health Relevance

These studies will provide fundamental information about how, where and when PD-L1 regulates tolerance, autoimmunity and immunopathology. The results of our studies will have implications for developing new therapies for human malignancies, chronic infections, and autoimmune diseases, and increasing success of transplantation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI040614-16A1
Application #
8630055
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Rothermel, Annette L
Project Start
1997-02-01
Project End
2018-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
16
Fiscal Year
2014
Total Cost
$381,375
Indirect Cost
$156,375
Name
Harvard University
Department
None
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
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
Tarrio, Margarite L; Grabie, Nir; Bu, De-xiu et al. (2012) PD-1 protects against inflammation and myocyte damage in T cell-mediated myocarditis. J Immunol 188:4876-84
Bu, De-xiu; Tarrio, Margarite; Maganto-Garcia, Elena et al. (2011) Impairment of the programmed cell death-1 pathway increases atherosclerotic lesion development and inflammation. Arterioscler Thromb Vasc Biol 31:1100-7
Jin, Yiping; Chauhan, Sunil K; El Annan, Jaafar et al. (2011) A novel function for programmed death ligand-1 regulation of angiogenesis. Am J Pathol 178:1922-9
Good-Jacobson, Kim L; Szumilas, Courtney G; Chen, Lieping et al. (2010) PD-1 regulates germinal center B cell survival and the formation and affinity of long-lived plasma cells. Nat Immunol 11:535-42
Francisco, Loise M; Salinas, Victor H; Brown, Keturah E et al. (2009) PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med 206:3015-29
Sharpe, Arlene H (2009) Mechanisms of costimulation. Immunol Rev 229:5-11
Keir, Mary E; Freeman, Gordon J; Sharpe, Arlene H (2007) PD-1 regulates self-reactive CD8+ T cell responses to antigen in lymph nodes and tissues. J Immunol 179:5064-70
Butte, Manish J; Keir, Mary E; Phamduy, Theresa B et al. (2007) Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 27:111-22
Read, Simon; Greenwald, Rebecca; Izcue, Ana et al. (2006) Blockade of CTLA-4 on CD4+CD25+ regulatory T cells abrogates their function in vivo. J Immunol 177:4376-83

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