MicroRNA-146a controls functional plasticity in γδ T cells by targeting NOD1

Abstract

γδ T cells are major providers of proinflammatory cytokines. They are preprogrammed in the mouse thymus into distinct subsets producing either interleukin-17 (IL-17) or interferon-γ (IFN-γ), which segregate with CD27 expression. In the periphery, CD27^- γδ (γδ27^-) T cells can be induced under inflammatory conditions to coexpress IL-17 and IFN-γ; the molecular basis of this functional plasticity remains to be determined. On the basis of differential microRNA (miRNA) expression analysis and modulation in γδ T cell subsets, we identified miR-146a as a thymically imprinted post-transcriptional brake to limit IFN-γ expression in γδ27^- T cells in vitro and in vivo. On the basis of biochemical purification of Argonaute 2-bound miR-146a targets, we identified <i>Nod1</i> to be a relevant mRNA target that regulates γδ T cell plasticity. In line with this, <i>Nod1</i>-deficient mice lacked multifunctional IL-17⁺ IFN-γ⁺ γδ27^- cells and were more susceptible to <i>Listeria monocytogenes</i> infection. Our studies establish the miR-146a/NOD1 axis as a key determinant of γδ T cell effector functions and plasticity.