Transcription factor-driven regulation of ILC1 and ILC3

Abstract

Mammalian innate lymphoid cells (ILCs) have functional relevance under both homeostatic and disease settings, such as inflammatory bowel disease (IBD), particularly in the context of maintaining the integrity of mucosal surfaces. Early reports highlighted group 1 and 3 ILC regulatory transcription factors (TFs), T-box expressed in T cells (T-bet; Tbx21) and RAR-related orphan nuclear receptor γt (RORγt; Rorc), as key regulators of ILC biology. Since then, other canonical TFs have been shown to have a role in the development and function of ILC subsets. In this review, we focus on recent insights into the balance between mature ILC1 and ILC3 based on these TFs and how they interact with other key cell-intrinsic molecular pathways. We outline how this TF interplay might be explored to identify novel candidate therapeutic avenues for human diseases.

Keywords: innate lymphoid cells; transcription factor.

Figure 1

Group 1 innate lymphoid cell (ILC1) heterogeneity across tissues in mice. ILC1 are heterogenous depending on the key requirement for either T-box expressed in T cells (T-bet) or Homolog of Blimp-1 in T cells (Hobit) for development and maintenance. These ILC1 subsets are located in distinct anatomical sites. Hepatic granzyme C⁺ ILC1 require T-bet for maintenance; however, the role of Hobit in these cells remains to be verified. Figure created using BioRender (https://biorender.com).

Figure 2

Key figure. Model of transcription factor (TF) interplay regulating Group 3 innate lymphoid cell (ILC3)–Group 1 innate lymphoid cell (ILC1) plasticity in mice and humans. TGFβ crucially regulates natural killer (NK) cell plasticity toward Hobit-expressing ILC1, which may present Hobit-dependent ILC1. The relationship of Homolog of Blimp-1 in T cells (Hobit)- and T-box expressed in T cells (T-bet)-dependent ILC1 remains unknown, as does whether plasticity exists between these ILC1 subsets. Plasticity between T-bet-dependent ILC1 and ILC3 is regulated by a TF interplay, as depicted. T-bet and RAR-related orphan nuclear receptor γt (RORγt) regulate each other, and c-musculoaponeurotic fibrosarcoma(c-Maf) and hypoxia-inducible factor (HIF) 1 can directly inhibit T-bet expression. Whether T-bet is also directly regulated by B cell lymphoma 6 (BCL6)-inhibited RORα and whether Aiolos and the c-Maf-controlled BCL6 inhibit RORγt remains to be determined. RORγt⁺ lymphoid tissue inducer cells (LTi) ILC3 are not believed to express T-bet; however, T-bet-expressing LTi ILC3 have been observed in c-Maf-deficient mice. Figure created using BioRender (https://biorender.com). Abbreviation: DN, double negative.