MicroRNA-126 deficiency enhanced the activation and function of CD4+T cells by elevating IRS-1 pathway

Abstract

Recent evidence showed that microRNA-126 (miR-126) has been involved in the development and function of immune cells, which contributed to the pathogenesis of related clinical diseases. However, the potential role of miR-126 in the development and function of CD4⁺T cells remains largely unknown. Here we firstly found that the activation and proliferation, as well as the expression of IFN-γ, of CD4⁺T cells from miR-126 knockdown (KD) mice using miRNA-Sponge technique were enhanced significantly in vitro, compared with those in CD4⁺T cells from wild type (WT) mice. To further monitor the possible effect of miR-126 deficiency on the function of CD4⁺T cells in vivo, we used dextran sulfate sodium (DSS)-induced murine model of acute autoimmune colitis and found that miR-126 deficiency could elevate the pathology of colitis. Importantly, the proportion of CD4⁺T cells in splenocytes increased significantly in miR-126KD mice. Moreover, the expression levels of CD69 and CD44 on CD4⁺T cells increased obviously and CD62L expression decreased significantly. Of note, adoptive cell transfer assay showed that the pathology of colitis was more serious in CFSE-labeled miR-126KD CD4⁺T cells transferred group, compared with that in CFSE-labeled WT CD4⁺T cells transferred group. Consistently, the expression levels of CD69 and CD44 on CFSE⁺ cells increased significantly. Furthermore, both the proliferation and IFN-γ secretion of CFSE⁺ cells also increased significantly in CFSE-labeled miR-126KD CD4⁺T cells transferred group. Mechanistic evidence showed that the expression of insulin receptor substrate 1 (IRS-1), as a functional target of miR-126, was elevated in CD4⁺T cells from miR-126KD mice, accompanied by altered transduction of ERK, AKT and NF-κB pathway. Our data revealed a novel role in which miR-126 was an intrinsic regulator in the function of CD4⁺T cells, which provided preliminary basis for further exploring on the role of miR-126 in the development, function of CD4⁺T cells and related clinical diseases.