@article{oai:showa.repo.nii.ac.jp:00003461,
 author = {MAEDA, Kohei and TANIOKA, Toshihiro and IWAMOTO, Sanju},
 issue = {2},
 journal = {The Showa University journal of medical sciences},
 month = {2020-07, 2020-08-19},
 note = {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. In experiments of cytokine-mediated modulation of Th17 cell differentiation, IL-4 suppressed the conversion of CD31+ CCR6- naive T cells into CD31- CCR6+ Th17 precursors by upregulating CD31 expression and suppressing CCR6 expression. In conclusion, CD31- CCR6+ Th17 precursors could be sourced from CD31+ CCR6- naive T cells, and IL-4 regulated the early Th17 differentiation. Our 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.},
 pages = {135--145},
 title = {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},
 volume = {32},
 year = {}
}