MicroRNA-181a regulates IFN-γ expression in effector CD8+ T cell differentiation

Abstract

CD8 + T cells are key players in immunity against intracellular infections and tumors. The main cytokine associated with these protective responses is interferon-γ (IFN-γ), whose production is known to be regulated at the transcriptional level during CD8 + T cell differentiation. Here we found that microRNAs constitute a posttranscriptional brake to IFN-γ expression by CD8 + T cells, since the genetic interference with the Dicer processing machinery resulted in the overproduction of IFN-γ by both thymic and peripheral CD8 + T cells. Using a gene reporter mouse for IFN-γ locus activity, we compared the microRNA repertoires associated with the presence or absence of IFN-γ expression. This allowed us to identify a set of candidates, including miR-181a and miR-451, which were functionally tested in overexpression experiments using synthetic mimics in peripheral CD8 + T cell cultures. We found that miR-181a limits IFN-γ production by suppressing the expression of the transcription factor Id2, which in turn promotes the Ifng expression program. Importantly, upon MuHV-4 challenge, miR-181a-deficient mice showed a more vigorous IFN-γ + CD8 + T cell response and were able to control viral infection significantly more efficiently than control mice. These data collectively establish a novel role for miR-181a in regulating IFN-γ-mediated effector CD8 + T cell responses in vitro and in vivo.

MicroRNA miR-181—A Rheostat for TCR Signaling in Thymic Selection and Peripheral T-Cell Function

“…Consistently, loss of miR-181a/b-1 in peripheral T cells resulted in upregulation of DUSP6 and limited phosphorylation of Erk [ 89 ]. Interestingly, another study reported improved viral clearance in a model of murid gammaherpesvirus 4 infection and a concomitant increase in activated CD8 T cells [ 90 ]. The reason for this apparent discrepancy remains unclear.…”

“…Loss of miR-181a/b-1 results in delayed clearance of LCMV after infection due to a limited CD8 T cell response [ 89 ]. Conversely, miR-181a/b-1-deficiency improved the clearance of murid gammaherpesvirus 4 [ 90 ]. The latter was attributed to elevated levels of IFNγ produced in the absence of miR-181a/b-1, presumably via derepression of Id2.…”

Oclacitinib, a Janus Kinase Inhibitor, Reduces the Frequency of IL-4- and IL-10-, but Not IFN-γ-, Producing Murine CD4+ and CD8+ T Cells and Counteracts the Induction of Type 1 Regulatory T Cells

“…In general, Th1 cells primarily enhance the cell-mediated immune response to intracellular pathogens through the synthesis of pro-inflammatory Th1 cytokines, especially IFN-γ. Similarly, CD8 + T cells, especially Tc1 cells, play a critical role in the immunity against intracellular infections and tumors, and IFN-γ is the main cytokine associated with these protective responses [ 42 ]. Although Tc17 cells are known to contribute to the mediation of pathologic inflammation and autoimmune processes, they are also involved in protective immune responses against fungi, viruses and bacteria [ 43 ].…”

Emerging Role of Non-Coding RNAs in Regulation of T-Lymphocyte Function

“…Overexpression of miR-181c has suppressed activation of T cell, impaired cytoskeleton arrangement in T cells by targeting BRK1 ( 23 ). Meanwhile, miR-181a has been reported to restrict IFN-γ production by targeting Id2 so regulating IFN-γ-mediated CD8+ T cell responses mediated by ( 24 ). This miRNA also promotes expression of TGF-β and IL-10 and inhibits function of Tregs through modulating the PI3K/Akt pathway ( 25 ).…”