Regulatory Effect of IL-4 on Early Th17 Differentiation from Naive T Cells into Stem Cell Memory Th17 Precursors via Modulation of CD31 and CCR6 Expression

: Although antigen-specific T helper （ Th ） cells are developed from naive T cells, human Th17 cells are not derived from naive CD4 + T cells unlike murine cells. Therefore, the source of human Th17 cells has remained unresolved. In this study, we assessed the early differentiation pathway of human Th17 cells from CD31 + thymic naive T cells into stem cell memory CCR6 + Th17 precursors and the regulation of this process by cytokines. Peripheral blood mononuclear cells were isolated from healthy volunteers. We found that only CD31 - CCR6 + naive type CD4 + T cells had the ability to produce IL-17A in response to Th17-inducing stimuli. A cell tracking assay using CD31 + CCR6 - cells labeled with carboxyfluorescein diacetate succinimidyl ester revealed that CD31 - CCR6 + Th17 precursors were derived from CD31 + CCR6 - thymic naive T cells. CD31 is known to suppress IL-17 production by interfering with downstream T cell receptor （ TCR ） signaling molecules including Lck, which is essential for IL-17 production. The inactive form of Lck was much higher in CD31 + T cells than CD31 - T cells after TCR stimulation. cell the conversion of CD31 + CCR6 - naive T cells into CD31 - CCR6 + Th17 precursors by upregulating CD31 expression and suppressing CCR6 expression. In CD31 - CCR6 + Th17 precursors could be sourced from CD31 + CCR6 - naive T cells, and IL-4 the early Th17 findings provide novel insights into the regulation of differentiation of naive CD4 + T cells into Th17 cells in humans. Furthermore, our results may provide hints for further elucidation of the differentiation process of Th17 cells and of the pathology of Th17 cell-related diseases.