Deciphering the transcriptional switches of innate lymphoid cell programming: the right factors at the right time

Innate lymphoid cells (ILCs) are increasingly recognised as an innate immune counterpart of adaptive T(H) cells. In addition to their similar effector cytokine production, there is a strong parallel between the transcription factors that control the differentiation of T(H)1, T(H)2 and T(H)17 cells and ILC Groups 1, 2 and 3, respectively. Here, we review the transcriptional circuit that specifies the development of a common ILC progenitor and its subsequent programming into distinct ILC groups. Notch, GATA-3, Nfil3 and Id2 are identified as early factors that suppress B and T cell potentials and are turned on in favour of ILC commitment. Natural killer cells, which are the cytotoxic ILCs, develop along a pathway distinct from the rest of the helper-like ILCs that are derived from a common progenitor to all helper-like innate lymphoid cells (CHILPs). PLZF(−) CHILPs give rise to lymphoid tissue inducer cells while PLZF(+) CHILPs have multi-lineage potential and could give rise to ILCs 1, 2 and 3. Such lineage specificity is dictated by the controlled expression of T-bet, RORα, RORγt and AHR. In addition to the type of transcription factors, the developmental stages at which these factors are expressed are crucial in specifying the fate of the ILCs.