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.
|Wu, Chuan; Chen, Zuojia; Xiao, Sheng et al. (2018) SGK1 Governs the Reciprocal Development of Th17 and Regulatory T Cells. Cell Rep 22:653-665|
|Wu, Chuan; Chen, Zuojia; Dardalhon, Valerie et al. (2017) The transcription factor musculin promotes the unidirectional development of peripheral Treg cells by suppressing the TH2 transcriptional program. Nat Immunol 18:344-353|
|Kishi, Yasuhiro; Kondo, Takaaki; Xiao, Sheng et al. (2016) Protein C receptor (PROCR) is a negative regulator of Th17 pathogenicity. J Exp Med 213:2489-2501|
|Meyer Zu Horste, Gerd; Wu, Chuan; Wang, Chao et al. (2016) RBPJ Controls Development of Pathogenic Th17 Cells by Regulating IL-23 Receptor Expression. Cell Rep 16:392-404|
|Yeung, M Y; Ding, Q; Brooks, C R et al. (2015) TIM-1 signaling is required for maintenance and induction of regulatory B cells. Am J Transplant 15:942-53|
|Yang, Li; Brooks, Craig R; Xiao, Sheng et al. (2015) KIM-1-mediated phagocytosis reduces acute injury to the kidney. J Clin Invest 125:1620-36|
|Zhu, Chen; Sakuishi, Kaori; Xiao, Sheng et al. (2015) An IL-27/NFIL3 signalling axis drives Tim-3 and IL-10 expression and T-cell dysfunction. Nat Commun 6:6072|
|Xiao, Sheng; Brooks, Craig R; Sobel, Raymond A et al. (2015) Tim-1 is essential for induction and maintenance of IL-10 in regulatory B cells and their regulation of tissue inflammation. J Immunol 194:1602-8|
|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|
|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|
Showing the most recent 10 out of 24 publications