Rarity of Human T Helper 17 Cells Is due to Retinoic Acid Orphan Receptor-Dependent Mechanisms that Limit Their Expansion

SummaryThe reason why CD4+ T helper 17 (Th17) cells, despite their well-known pathogenic role in chronic inflammatory disorders, are very rare in the inflammatory sites remains unclear. We demonstrate that human Th17 cells exhibit low ability to proliferate and to produce the T cell growth factor interleukin-2 (IL-2), in response to combined CD3 and CD28 stimulation. This was due to the upregulated expression of IL-4-induced gene 1 (IL4I1) mRNA, a secreted L-phenylalanine oxidase, which associated with a decrease in CD3ζ chain expression and consequent abnormalities in the molecular pathway that allows IL-2 production and cell proliferation. High IL4I1 mRNA expression was detectable in Th17 cell precursors and was strictly dependent on Th17 cell master gene, the retinoid acid related orphan receptor (RORC). Th17 cells also exhibited RORC-dependent CD28 hyperexpression and the ability to produce IL-17A after CD28 stimulation without CD3 triggering. Our findings suggest that the rarity of human Th17 cells in inflamed tissues results from RORC-dependent mechanisms limiting their expansion.

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► Human Th17 cells do not produce IL-2 in response to anti-CD3+CD28 stimulation
► Human Th17 cells express high amounts of the oxidase IL4I1 which impairs CD3 signaling
► IL4I1 is expressed by human Th17 cell precursors and its expression is RORC dependent
► CD28 triggering in absence of CD3 stimulation induces IL-17A production in Th17 cells