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.
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.
|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|
Showing the most recent 10 out of 18 publications