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

Abstract

Innate lymphoid cells (ILCs) are increasingly recognised as an innate immune counterpart of adaptive T-helper (TH) 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 (GATA-binding protein 3), Nfil3 (nuclear factor interleukin-3) and Id2 (inhibitor of DNA-binding 2) 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 ILCs (CHILPs). PLZF(-) (promyelocytic leukaemia zinc-finger) CHILPs give rise to lymphoid tissue inducer cells, while PLZF(+) CHILPs have multilineage potential and could give rise to ILCs 1, 2 and 3. Such lineage specificity is dictated by the controlled expression of T-bet (T-box expressed in T cells), RORα (retinoic acid receptor-related orphan nuclear receptor-α), RORγt (retinoic acid receptor-related orphan nuclear receptor-γt) and AHR (aryl hydrocarbon receptor). 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.

Figure 1. Schematic of the proposed transcriptional circuit regulating ILC development

ILC1s are grouped in blue and are divided into the helper ILC1s and cytotoxic ILC1s (NK cells), ILC2s are grouped in green, ILC3s in red and CHILPs in yellow. I.E. ILC1 = intraepithelial ILC1; L.P. ILC1 = lamina propria ILC1. B cells, T cells and all ILCs are derived from a multipotent CLP, with the decision to differentiate into any of these immune cell types dependent on the transcription factor that is turned on. Expression of EBF1 and Pax5 for example allows differentiation into a B cell (1). Expression of Nfil3 and Id2/Id3 (2) leads to an NK precursor that then progresses onto a mature cNK cell via a pathway that requires T-bet and Eomes. If Notch and GATA-3 are switched on instead (3), a multipotent ILC/T progenitor may be generated. Expression of TCF-1 by this progenitor (4) leads to a more restricted NK/T progenitor that continues to develop in the thymus. If Bcl11b is switched on, a T cell is generated, but sequential expression of Nfil3, Id2, T-bet and Eomes gives rise to tNK cells instead. ILC/T progenitors that otherwise express Nfil3 and Id2 become CHILPs (5). PLZF⁻ CHILPs develop into LTi cells, while PLZF⁺ CHILPs give rise to the remaining helper ILC1s, ILC2s and NCR^+/− ILC3s via the expression of lineage-specific transcription factors. These are T-bet for the ILC1s, GATA-3 and RORα for ILC2s and AHR and RORγt for ILC3s. CCR6⁻ NCR⁺ ILC3s demonstrate plasticity and can further differentiate to become an ILC1 by expressing T-bet. The origin of the I.E. ILC1 has not been determined.