Abstract
BackgroundFoxp3+CD4+ regulatory T cells (Treg) constitutes a key event in autoimmune diseases. STAT5b is the critical link between the IL-2/15 and FOXP3, the master regulator of Treg cells.MethodsThe CD3+T cell and Foxp3+CD4+ regulatory T cells were overexpressioned or knockdown MKL-1 and STAT5a and tested for Treg cell development and function. Direct interaction of MKL-1 and STAT5a were analyzed by coimmunoprecipitation assays, Luciferase assay, Immunofluoresence Staining and Yeast two-hybrid screening. The effect of MKL-1 and STAT5a on the Treg genes expression was analyzed by qPCR and western blotting and Flow cytometry.ResultsHowever, the molecular mechanisms mediating STAT5b-dependent Treg genes expression and Treg cell phenotype and function in autoimmune diseases are not well defined. Here, we report that the MKL-1 is a coactivator for the major Treg genes transcription factor STAT5b, which is required for human Treg cell phenotype and function. The N terminus of STAT5b, which contains a basic coiled-coil protein–protein interaction domain, binds the C-terminal activation domain of MKL-1 and enhances MKL-1 mediated transcriptional activation of Treg-specific, CArG containing promoters, including the Treg-specific genes Foxp3. Suppression of endogenous STAT5b expression by specific small interfering RNA attenuates MKL-1 transcriptional activation in cultured human cells. The STAT5b–MKL-1 interaction identifies a role of Treg-specific gene regulation and regulated mouse Treg cell development and function and suggests a possible mechanism for the protective effects of autoimmune disease Idiopathic Thrombocytopenic Purpura (ITP).ConclusionsOur studies demonstrate for the first time that MKL-1 is a coactivator for STAT5b, the regulator of Treg cell development and function.-iyKJXfczyP238CqvjMFToVideo abstract
Highlights
Foxp3+CD4+ regulatory T cells cover in Serum -free Medium (T cells) (Treg) constitutes a key event in autoimmune diseases
Megakaryoblastic leukemia 1 (MKL-1) and STAT5b are high expressed in Treg cells The expression levels of MKL-1, STAT5b and Foxp3 transcripts in human Peripheral blood mononuclear cells (PBMC), CD3+ T and Treg cells were detected by qPCR (Fig. 1a), with the highest mRNA and protein level of Foxp3 and CD25 (Supplemental Fig. 1C-E)
These data support that over-expression MKL-1 and STAT5b increase the number of Treg in CD3+ T cells and enhance the Treg markers expression
Summary
Foxp3+CD4+ regulatory T cells (Treg) constitutes a key event in autoimmune diseases. Methods: The CD3+T cell and Foxp3+CD4+ regulatory T cells were overexpressioned or knockdown MKL-1 and STAT5a and tested for Treg cell development and function. Foxp3+CD4+ regulatory T cells (Treg) have a crucial role in controlling CD4+ T-cell activation, proliferation, and effector function [1]. Treg constitutes a key event in the development of autoimmune diseases such as Idiopathic Thrombocytopenic Purpura (ITP) [2]. Recent studies have shown that MKL-1 in megakaryocyte differentiation is mediated by association with SRF [10]. Based on these findings, we have examined the effects of the MKL-1 in Treg cell phenotype and function
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