Mirlekar, B. and Ghorai, S. and Khetmalas, M. and Bopanna, R. and Chattopadhyay, S. (2015) Nuclear matrix protein SMAR1 control regulatory T-cell fate during inflammatory bowel disease (IBD). Mucosal Immunology. doi:10.1038. ISSN doi:10.1038/mi.2015.42

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Abstract

Regulatory T (Treg) cells are essential for self-tolerance and immune homeostasis. Transcription factor Foxp3, a positive regulator of Treg cell differentiation, has been studied to some extent. Signal transducer and activator of transcription factor 3 (STAT3) is known to negatively regulate Foxp3. It is not clear how STAT3 is regulated during Treg differentiation. We show that SMAR1, a known transcription factor and tumor suppressor, is directly involved in maintaining Treg cell fate decision. T-cell-specific conditional knockdown of SMAR1 exhibits increased susceptibility towards inflammatory disorders, such as colitis. The suppressive function of Treg cells is compromised in the absence of SMAR1 leading to increased T helper type 17 (Th17) differentiation and inflammation. Compared with wild-type, the SMAR1�/� Treg cells showed increased susceptibility of inflammatory bowel disease in Rag1�/� mice, indicating the role of SMAR1 in compromising Treg cell differentiation resulting in severe colitis. We show that SMAR1 negatively regulate STAT3 expression favoring Foxp3 expression and Treg cell differentiation. SMAR1 binds to theMARelement of STAT3 promoter, present adjacent to interleukin-6 response elements. Thus Foxp3, a major driver of Treg cell differentiation, is regulated by SMAR1 via STAT3 and a fine-tune balance between Treg and Th17 phenotype is maintained. INTRODUCTION Disruption of immune suppression contributes to progression of autoimmune diseases. Regulatory T (Treg) cells are essential for maintenance of immune homeostasis and organization of controlled immune responses.1 Dysregulated function of Treg cells could account for various immune disorders. In particular, it limits the magnitude of effector responses leading to failure to adequately control infection and inflammation.2 Treg cells also subside inflammation due to microbial immune responses, including commensals.3 Upon activation, naive CD4þ T cells differentiate into different lineages of helper T (Th) cells that are characterized by distinct developmental regulation and biological functions.4 Activation of naive T cells with immunoregulatory cytokine transforming growth factor (TGF)-b and pleotropic cytokine

Item Type:	Article
Subjects:	Infection and Immunity
Depositing User:	Mr. Rameshwar Nema
Date Deposited:	27 May 2015 07:20
Last Modified:	19 Feb 2016 08:58
URI:	http://nccs.sciencecentral.in/id/eprint/184

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