Distinct regulation of interleukin‐17 in human T helper lymphocytes

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Abstract
Objective Interleukin‐17 (IL‐17)–producing T helper cells have been proposed to represent a separate lineage of CD4+ cells, designated Th17 cells, which are regulated by the transcription factor retinoic acid–related orphan receptor γt (RORγt). However, despite advances in understanding murine Th17 differentiation, a systematic assessment of factors that promote the differentiation of naive human T cells to Th17 cells has not been reported. The present study was undertaken to assess the effects on naive human CD4+ T cells of cytokines known to promote murine Th17 cells. Methods Human naive and memory CD4+ T cells isolated from peripheral blood were activated and cultured with various cytokines. Cytokine production was measured by enzyme‐linked immunosorbent assay and flow cytometry. Messenger RNA was measured by quantitative polymerase chain reaction. Results In response to anti‐CD3/anti‐CD28 stimulation alone, human memory T cells rapidly produced IL‐17, whereas naive T cells expressed low levels. Transforming growth factor β1 and IL‐6 up‐regulated RORγt expression but did not induce Th17 differentiation of naive CD4+ T cells. However, IL‐23 up‐regulated its own receptor and was an important inducer of IL‐17 and IL‐22. Conclusion The present data demonstrate the differential regulation of IL‐17 and RORγt expression in human CD4+ T cells compared with murine cells. Optimal conditions for the development of IL‐17–producing T cells from murine naive precursors are ineffective in human T cells. Conversely, IL‐23 promoted the generation of human Th17 cells but was also a very potent inducer of other proinflammatory cytokines. These findings may have important implications in the pathogenesis of human autoimmunity as compared with mouse models.