MiR-568 inhibits the activation and function of CD4+ T cells and Treg cells by targeting NFAT5

Abstract

CD4(+) T cells play critical roles in orchestrating adaptive immune responses. Their activation and proliferation are critical steps that occur before they execute their biological functions. Despite the important role of this process, the underlying molecular events are not fully understood. MicroRNAs (miRNAs) have been shown to play important roles in lymphocyte development and function. However, the miRNAs that regulate T-cell differentiation, activation and proliferation are still largely unknown. In our previous study, using a miRNA array, we found that several miRNAs (including miR-202, 33b, 181c, 568 and 576) are differentially expressed between resting and activated CD4(+) T cells. In this study, we focused on the function of miR-568 during CD4(+) T-cell activation. We showed that the expression level of miR-568 decreased during the activation of T cells, including Jurkat cells and human peripheral blood CD4(+) T cells. When Jurkat or human peripheral blood CD4(+) T cells were transfected with miR-568 mimics, cell activation was significantly inhibited, as shown by the inhibited expression of activation markers such as CD25, CD69 and CD154; decreased IL-2 production; and inhibited cell proliferation. Using software predictions and confirmatory experiments, we demonstrated that nuclear factor of activated T cells 5 (NFAT5) is a target of miR-568. Treg cells are an important CD4(+) T-cell subpopulation, so we also evaluated the function of miR-568 in Treg-cell activation and differentiation. We showed that the miR-568 level decreased, while the NFAT5 protein level increased during CD4(+)CD25(+) Treg-cell activation, and the transfection of miR-568 mimics inhibited the NFAT5 expression, inhibited the production of both TGF-β and IL-10 and also inhibited the proliferation of Treg cells. Our further study showed that over-expression of miR-568 can inhibit Treg-cell differentiation and can inhibit the suppressive effect of these cells on effector cells. In addition, inhibition of NFAT5 by siRNA-mediated knockdown can inhibit the activation and differentiation of Treg cells. These findings reveal that miR-568 can inhibit the activation and function of both CD4(+) T cells and Treg cells by targeting NFAT5. Since miR-568 plays an important role in both CD4(+) T cells and Treg cells, these findings may provide leads for the development of novel treatments for human inflammatory and autoimmune diseases.

Expression pattern of key microRNAs in patients with newly diagnosed chronic myeloid leukemia in chronic phase

“…Moreover, we also showed that miR-568 is overexpressed in CML patients, which has not been previously reported in chronic phase of CML. miR-568 has a role in the activation of CD4 + T cells and, unlike our upward trend in CML, it is downregulated CLL [47,48]. Different expression patterns of miR-568 in CML and CLL could be due to the origin of their lineage in bone marrow.…”

Exosomes and tumor-mediated immune suppression

“…The transfer of miRs from tumor to immune cells alters their functions, usually downregulating antitumor activities and promoting tumorigenesis (84). Tumor-associated miRs, such as miR-21, miR-155, miR-146a, and miR-568, which have been frequently identified as components of the TEX cargo, regulate the differentiation and functions of various immune cells, often inhibiting effector functions or inducing apoptosis (87)(88)(89)(90)(91). Exosomes in the plasma of patients with different cancer types carry distinct, cancer-specific miR signatures, which appear to correlate with the cancer progression and responses to therapy (92,93).…”

NFAT5 Has a Job in the Brain

“…NFAT5 also promoted the activation of Tregs by upregulating the expression of IL-2. When NFAT5 was knocked out, the proliferation of Tregs and the production of IL-10 were also inhibited [47]. It is highly like that NFAT5 maintained a balance between different T cell subsets.…”