Nr4a1 plays a crucial modulatory role in Th1/Th17 cell responses and CNS autoimmunity

Nuclear receptor4 group A1 (Nr4a1), an orphan nuclear receptor, is down-regulated in peripheral blood mononuclear cells (MNCs) of individuals with multiple sclerosis (MS), and Nr4a1 deficiency results in severe experimental autoimmune encephalomyelitis (EAE), an animal model of MS, caused by increased macrophage infiltration into the central nervous system (CNS). However, the role of Nr4a1 in macrophage phenotype and T cell responses remains poorly understood. In the present study we show that macrophages/microglia of Nr4a1^-/- mice, which exhibited earlier onset and more severe clinical EAE, were polarized to an enhanced type 1 (M1) phenotype and produced higher levels of IL-12 and TNF-α than wild type mice. Significantly increased numbers of CD4⁺ T cells and frequency of CD4⁺IFN-γ⁺ and CD4⁺IL-17⁺ T cells were observed in the CNS and spleen of Nr4a1^-/- mice, with decreased percentages of apoptosis in CD4⁺ T cells. The percentages of CD4⁺Foxp3⁺ Treg cells in the CNS of Nr4a1^-/- mice were also reduced. Furthermore, purified CD4⁺ T cells from naïve Nr4a1^-/- mice exhibited enhanced Th1 and Th17 differentiation capacity, and MOG-reactive Th17 cells from Nr4a1^-/- mice adoptively transferred more severe EAE in recipient mice. Our results, for the first time, demonstrate that Nr4a1 not only induces Type 2 macrophages/microglia phenotype, but is also a critical inhibitory molecule for Th1/Th17 cell differentiation. This finding indicates that Nr4a1-related molecule(s) may have therapeutic potential in MS and likely other autoimmune disorders.