OX40 signaling activates epigenetic mechanisms to repress Th17 cells and Th17-related autoimmune diseases (LYM5P.708)

Abstract

Abstract Th17 cells produce copious amount of IL-17, which mediates host antimicrobial responses and autoimmune diseases. The exact mechanisms that control Th17 homeostasis, especially those that inhibit Th17 differentiation, remain incompletely defined. Here, we found that the T cell costimulatory molecule OX40 is a potent repressor of Th17 cells and Th17-mediated autoimmune disease. Under Th17-polarizing conditions in vitro, engagement of OX40 strongly inhibited IL-17 production despite enhanced cell survival and proliferation. Mechanistically, OX40 engagement induced sustained activation of both canonical and non-canonical NF-kB pathways, and it is RelB that mediated dominant suppression of Th17 cells that is independent of p52 and p50. RelB directly recruited H3K9 methyltransferases G9a and Setdb1 upon binding to IL-17 locus, and this resulted in di- and tri-methylation of H3K9, which led to a closed epigenetic configuration of IL-17 locus that prevents RORγt binding to IL-17 locus. Conversely, inhibition of histone methyltransferase activity significantly reversed OX40-mediated suppression of Th17 cells. Importantly, in an EAE model, stimulation of OX40 in vivo inhibited the disease process, while RelB-deficient CD4+ T cells induced exacerbated disease. In conclusion, our study identified a new mechanism in the control of Th17 cells, and this mechanism relies on OX40 induced repressive epigenetic process. This finding may have important therapeutic implications in the clinic.