Expression of the orphan nuclear receptor NR4A2 is required for IL-17 production by Th17 cells and the induction of Th17-mediated autoimmunity (93.14)

Abstract

Previously, we reported that NR4A2, an orphan nuclear receptor, is upregulated by peripheral blood cells during the human autoimmune disease multiple sclerosis (MS), as well as by peripheral blood cells and leukocytes infiltrating the central nervous system (CNS) during experimental autoimmune encecephalomyelitis (EAE). The pathology of MS and EAE is mediated by infiltration of both Th1 and Th17 cells into the CNS, but we reveal that upregulation of NR4A2 observed in CNS-infiltrating leukocytes and peripheral blood cells is most apparent amongst IL-17-secreting CD4+ T cells. Therefore, we examined the role of NR4A2 in the differentiation of these Th17 cells: transfection of naïve T cells with NR4A2 siRNA precludes IL-17 secretion when cultured under Th17 polarising conditions. However, such cells do proliferate and upregulate RORγt to the same extent as fully functional Th17 cells. IL-23 stimulation is critical in licensing IL-17 production by Th17 cells and that this depends on the upregulation of IL-23R by Th17 cells subsequent to autocrine IL-21 signalling. NR4A2 siRNA knock-down in CD4+ T cells prevents IL-21 production under Th17 polarising conditions and consequently such cells do not upregulate IL-23R. Addition of exogenous IL-21 circumvented NR4A2 knock-down, leading to IL-23R upregulation and IL-17 production. Furthermore, NR4A2 appears to be critical in generating Th17-mediated autoimmunity as systemic administration of NR4A2 siRNA prevented EAE induction.