The T cell immunoglobulin and mucin domain (Tim) family of proteins have important and broad immune functions. Of these family members, Tim-1 was first identified to be expressed on activated CD4+ T cells and regulates Th2 responses and Th2-driven airway hyper-sensitivity. We and others have shown that manipulating Tim-1 signaling also regulates experimental autoimmune encephalomyelitis (EAE) and allogeneic transplant tolerance via mediating the development and/or function of Th1, Th17 and Treg cells. Almost all functional data on the biology of Tim-1 in T cells in these studies were obtained using different anti-Tim-1 antibodies that were either analyzed in vitro in the presence of antigen-presenting cells (APCs) or in vivo in animal models of the above mentioned diseases. I have recently found that Tim-1 is constitutively expressed on dendritic cells (DCs). I have also generated Tim-1 knockout mice and my preliminary data indicates that loss of Tim-1 affects both DC function and T cell responses. Because DCs play a central role in regulating T cell responses, my preliminary data suggests that the different T cell responses observed in previous studies may be due to the effect of Tim-1 on T cells or DCs, or both. Studies have suggested that both CD4+ T cells and DCs play key roles in the pathogenesis of colitis. However, whether Tim-1 plays a role in the pathogenesis of colitis is not known. Therefore, I will utilize Tim-1 knockout mice to systematically analyze the role of Tim-1 in regulating CD4+ T cell and DC responses and the development of colitis in animal models. The proposed study will advance our understanding of Tim-1 in immune regulation, which will have important implications for the development of novel therapeutic strategies for autoimmune diseases and chronic inflammatory conditions.
Autoimmune disease is caused by a dysregulated immune response. Tim-1 is a cell surface molecule expressed on immune cells and plays an important role in regulating immune responses. Here, I propose to study the effect and mechanism of Tim-1 in regulating immune responses and autoimmune diseases. Our ultimate goal is to determine whether Tim-1 could be targeted therapeutically for the treatment of autoimmune diseases.
|Kofler, David M; Marson, Alexander; Dominguez-Villar, Margarita et al. (2014) Decreased RORC-dependent silencing of prostaglandin receptor EP2 induces autoimmune Th17 cells. J Clin Invest 124:2513-22|
|Angiari, Stefano; Donnarumma, Tiziano; Rossi, Barbara et al. (2014) TIM-1 glycoprotein binds the adhesion receptor P-selectin and mediates T cell trafficking during inflammation and autoimmunity. Immunity 40:542-53|
|Joller, Nicole; Lozano, Ester; Burkett, Patrick R et al. (2014) Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses. Immunity 40:569-81|
|Wu, Chuan; Thalhamer, Theresa; Franca, Rafael F et al. (2014) Galectin-9-CD44 interaction enhances stability and function of adaptive regulatory T cells. Immunity 41:270-82|
|Xiao, Sheng; Yosef, Nir; Yang, Jianfei et al. (2014) Small-molecule ROR?t antagonists inhibit T helper 17 cell transcriptional network by divergent mechanisms. Immunity 40:477-89|
|Humphreys, Benjamin D; Xu, Fengfeng; Sabbisetti, Venkata et al. (2013) Chronic epithelial kidney injury molecule-1 expression causes murine kidney fibrosis. J Clin Invest 123:4023-35|
|Wu, Chuan; Yosef, Nir; Thalhamer, Theresa et al. (2013) Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature 496:513-7|
|Wu, Chuan; Pot, Caroline; Apetoh, Lionel et al. (2013) Metallothioneins negatively regulate IL-27-induced type 1 regulatory T-cell differentiation. Proc Natl Acad Sci U S A 110:7802-7|
|Xiao, Sheng; Zhu, Bing; Jin, Hulin et al. (2011) Tim-1 stimulation of dendritic cells regulates the balance between effector and regulatory T cells. Eur J Immunol 41:1539-49|