Transcriptional control of ILC identity

Abstract

Innate lymphoid cells (ILCs) are heterogeneous innate immune cells which participate in host defense, mucosal repair and immunopathology by producing effector cytokines similarly to their adaptive immune cell counterparts. The development of ILC1, 2, and 3 subsets is controlled by core transcription factors: T-bet, GATA3, and RORγt, respectively. ILCs can undergo plasticity and transdifferentiate to other ILC subsets in response to invading pathogens and changes in local tissue environment. Accumulating evidence suggests that the plasticity and the maintenance of ILC identity is controlled by a balance between these and additional transcription factors such as STATs, Batf, Ikaros, Runx3, c-Maf, Bcl11b, and Zbtb46, activated in response to lineage-guiding cytokines. However, how interplay between these transcription factors leads to ILC plasticity and the maintenance of ILC identity remains hypothetical. In this review, we discuss recent advances in understanding transcriptional regulation of ILCs in homeostatic and inflammatory conditions.

Keywords: ILC identity; ILC plasticity; innate lymphoid cells; transcription factor; transcriptional regulation.

Figure 1

ILC subsets are defined by core transcription factors. NK cells express natural cytotoxicity receptors (NCRs) and require Eomes and T-bet for their development. Eomes and T-bet maintain NK cell effector functions by inducing granzymes, perforin 1, and IFNγ. ILC1 development and maintenance depends on T-bet, which is required for IFNγ production. ILC2s require GATA3 for their development and maintenance. Bcl11b promotes ILC2 development by controlling ILC2 lineage associated genes and by restraining ILC3 development. RORα, Bcl11b and GATA3 control production of type 2 effector cytokines, IL-5, IL-13 and IL-4 in ILC2. ILC3s and LTi cells express RORγt, which is required for their development and maintenance. RORγt with RORα induce type 3 effector cytokines, IL-17 and IL-22. ILC3s are divided on NCR⁺ and NCR^- subsets. Development of NCR⁺ ILC3s depends on GATA3 and T-bet. GATA3 together with RORγt regulate IL-22. LTi cells express CCR6. Plasticity between ILC subsets is shown by dashed black arrows.

Figure 2

Transcriptional regulation of ILC1s and NK cells. (A) NK↔ILC1 plasticity. Tumors and mucosal pathogens, such as toxoplasma can induce IL-12 and TGF-β production by DCs and macrophages to drive NK↔ILC1 plasticity. NK↔ILC1 conversion is controlled by upregulation of T-bet and downregulation of Eomes. The ability of ILC1-like cells to convert back to NK cells remains unknown. (B) Maintenance of ILC1 identity. T-bet is required for ILC1s to produce IFNγ. IL-12R signaling activates STAT4, which induces T-bet transcription. Activated STAT4 also binds to Runx3 and IFNγ promoters to induce expression. Runx3 can also promote expression of IL12Rb1 thereby amplifying IL-12R signaling. T-bet associates with Runx3 to drive IFNγ transcription. IL-12R/STAT4 signaling maintains ILC1 phenotype via inducing T-bet and Runx3 for IFNγ production.

Figure 3

Transcriptional regulation of ILC3s. (A) ILC1↔ILC3 plasticity. Enteric pathogens, such as Salmonella and Campylobacter can induce ILC3→ILC1 plasticity. ILC3→ILC1 conversion is driven by IL-12 and IL-1β, produced by DCs and macrophages which leads to downregulation of RORγt and upregulation of T-bet expression. The reverse ILC1→ILC3 conversion can be induced by IL-23, IL-1β and retinoic acid (RA). Aiolos, c-Maf and Batf regulate ILC3↔ILC1 plasticity: Aiolos maintains ILC1 phenotype whereas c-Maf and Batf promote ILC3 phenotype. (B) Maintenance of ILC3 identity. RORγt is critical for NCR⁺ ILC3s to produce IL-22 and IL-17. IL-23 binds to IL-23R to activate STAT3, inducing RORγt. IL-6-IL6R signaling can induce STAT3 activation. Activated STAT3 induces transcription of c-Maf and/or Batf, each of them can bind to T-bet locus bind to T-bet locus, preventing T-bet transcription and acquisition of ILC1 phenotype. Batf and c-Maf individually or synergistically induce RORγt expression in T cells, however their ability to drive RORγt expression in ILC3s has not been shown yet. GATA3 limits RORγt expression by direct binding to RORγt gene locus. GATA3 and RORα can cooperate with RORγt to induce IL-22 production.

Figure 4

Transcriptional regulation of ILC2s. (A) ILC1↔ILC2 plasticity. Mucosal pathogens, such as M. tuberculosis can induce production of IL-12, IL-1β to drive ILC2→ILC1 plasticity. ILC2→ILC1 conversion is controlled by downregulation of GATA3 and upregulation of T-bet. Batf supports ILC2 maintenance. ILC2→ILC1 conversion can be reversed by IL-4. (B) ILC2↔ILC3 plasticity. Helminths, such as N. brasiliensis induce IL-1, IL-23, and TGF-β to promote ILC2→ILC3 conversion. Upregulation of RORγt results in acquisition of ILC3-like phenotype. Vitamin D3 prevents the conversion of ILC2 into IL-17 producing ILC3-like cells, possibly by reducing IL-23R expression on ILC3s and limiting acquisition of RORγt. ILC2→ILC3 conversion can be reversed by IL-4, which induces GATA3 expression. (C) Maintenance of ILC2 identity. GATA3 is critical for type 2 cytokine production: IL-5, IL-4, IL-13. IL-4 binds to IL-4R leading to activation of STAT6 which induces GATA3 transcription. GATA3 induces production of IL-5, IL-13, IL-4, IL-9. GATA3 can increase expression of IL-33R which leads to Batf upregulation. Batf may further support maintenance of ILC2 phenotype by promoting GATA3 expression. STAT5 activation by IL-2 and IL-7 can upregulate GATA3 expression. In addition to GATA3, RORα support IL-13 and IL-5 production by ILC2s. Bcl11b may support ILC2 phenotype by suppressing Ahr and promoting Gfi1, RORα and GATA3 expression.