Aiolos and T-bet cooperate to repress the ILC3 transcriptional program in human innate lymphocytes

Abstract

Abstract Innate lymphoid cells (ILCs) are tissue-resident lymphocytes devoid of antigen-specific receptors that provide an immediate source of cytokines in early immune responses and are enriched in mucosal tissues. Human ILC3s that produce the cytokine interleukin-22 and express the transcription factor RORγt have been shown to be able to convert into ILC1-like cells that produce mainly IFN-γ and express T-bet, in vitro. Whether this conversion also occurs in vivo remains unclear. In the present study we found that ILC3s and ILC1s in human tonsils represented the ends of a spectrum that included additional discrete subsets with intermediate transcriptional signatures. This finding strongly suggests that the ILC3 to ILC1-like conversion also occurs in vivo in humans. Gene expression analysis showed that the transcription factors Aiolos and T-bet were induced in the subsets closer to the canonical ILC1 subset. Chromatin studies indicated that Aiolos and T-bet cooperate to repress regulatory elements active in ILC3s. Ectopic expression of Aiolos and T-bet in the ILC3-like cell line MNK-3 repressed the production of IL-22 and induced IFN-γ. We conclude that Aiolos and T-bet cooperate to repress the ILC3 transcriptional program therefore contributing to the ILC3 to ILC1-like conversion.