Unlike αβ T cells, γδ T cells, LTi cells and NKT cells do not require IRF4 for the production of IL‐17A and IL‐22

Apart from conventional CD4+ Th17 cells, the cytokines IL‐17A and IL‐22 can also be produced by γδ T cells, NK cells and lymphoid tissue inducer (LTi) cells. Th17 cells develop from precursor cells after T‐cell receptor stimulation in the presence of TGF‐β, IL‐6 and IL‐23. In contrast, a subset of γδ T cells (“γδT17”) is committed for fast IL‐17 production already in the thymus; however, γδ T cells can also produce IL‐17 after prolonged in vitro stimulation via their γδ T‐cell receptor plus IL‐23. Here, we show that γδ T‐, LTi‐ and NKT cells differ extensively from Th17 cells in their signalling requirements for the generation of IL‐17A and IL‐22. While production of these cytokines by Th17 cells totally depends on the transcription factor interferon regulatory factor 4 (IRF4), IRF4 is irrelevant in the other cell types. As for γδ T cells, this finding pertains to both thymic commitment and prolonged in vitro culture. Furthermore, IL‐17A‐producing γδ T cells accumulate in the central nervous system of IRF4 deficient (Irf4−/−) mice during experimental autoimmune encephalomyelitis. IL‐17A‐producing WT and Irf4−/− γδ T cells equally express CCR6 and lack CD27. The underlying IRF4‐independent pathway partially involves STAT3 during in vitro stimulation.