FcR(+)CD4(+) T Cells as a Specific Subset of IL-17-producing Cells Controlled by BATF/IRF8: Novel Insights Into Etiology of Kawasaki Disease

Kawasaki disease (KD) is an acute vasculitis primarily involved coronary arteries of infants and children. Although more than 40 years have passed since the first description of the disease, its etiology remains unclear. Circulating interleukin 17 is increased in the acute stage of KD and expressed in the damaged coronary arterial wall from autopsies of children after KD. The aim of this study was to elucidate the involvement of IL-17 in the pathogenesis of KD. In this study, we identified a specific subset of CD4 + T cell expressing Fc receptor which existed high percentage in acute stage of KD than in recover stage. In addition, FcR + CD4 + T cell in acute stage expressed higher level of IL-17 than in recover stage. Therefore, we suggest this IL-17-producing FcR + CD4 + T cell may be a critical regulator of immunity in Kawasaki disease. In order to investigate the detail mechanism that FcR + CD4 + T cell subset expressed higher amount of IL-17 in KD, we isolated FcR - CD4 + and FcR + CD4 + T cells from adult healthy donors and stimulated with anti-CD3/CD28 beads only. We found that FcR + CD4 + T cells produced much higher IL-17 than FcR - CD4 + T cells without the need of Th17-differentiation cytokine. Furthermore, FcR + CD4 + T cells expressed higher IL-17-related transcriptional activator, BATF and lower level of transcriptional repress, IRF8 than FcR - CD4 + T cells. Knockdown of BATF and IRF8 could reduce and increase IL-17 production, respectively. These findings define BATF and IRF8 as the intrinsic transcriptional regulators in IL-17 production from FcR + CD4 + T cells. Collectively, our results suggest that IL-17-producing FcR + CD4 + T cells are the novel subset of IL-17-producing cells and important pathogenic immune cells in KD. Inhibition of IL-17 production from FcR + CD4 + T cells has great potential to be as a therapeutic strategy for Kawasaki disease and other FcR + CD4 + T cell-driven autoimmune diseases.