The role of retinoic acid‐related orphan receptor variant 2 and IL‐17 in the development and function of human CD4+ T cells

Abstract

AbstractTh17 cells are defined by their capacity to produce IL‐17, and are important mediators of inflammation and autoimmunity. Human Th17 cells express high levels of the retinoic acid‐related orphan receptor variant 2 (RORC2), but it is currently unclear whether expression of this transcription factor alone is sufficient to recapitulate all the known properties of Th17 cells. We used lentivirus‐mediated transduction to investigate the role of RORC2 in defining aspects of the human Th17 cell lineage. Expression of RORC2 induced production of IL‐17A, IL‐22, IL‐6 and TNF‐α, a Th17‐cell‐associated chemokine receptor profile and upregulation of CD161. RORC2‐transduced T cells were hypo‐responsive to TCR‐mediated stimulation, a property shared with ex vivo Th17 cells and overcome by addition of exogenous IL‐2 or IL‐15. Co‐culture experiments revealed that RORC2‐expressing cells were partially resistant to Treg cells since production of IL‐17 and proliferation were not suppressed. Evidence that IL‐17 stimulates CD4+ T cells to produce IL‐2 and proliferate suggested that the resistance of Th17 cells to Treg‐mediated suppression may be partly attributed to IL‐17 itself. These findings demonstrate that expression of RORC2 in T cells has functional consequences beyond altering cytokine production and provides insight into the factors regulating the development of human Th17 cells.

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