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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DK090105-02
Application #
8241944
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2011-03-15
Project End
2015-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
2
Fiscal Year
2012
Total Cost
$159,435
Indirect Cost
$11,810
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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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
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

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