NCR⁺ ILC3 maintain larger STAT4 reservoir via T‐BET to regulate type 1 features upon IL‐23 stimulation in mice

Abstract

Innate lymphoid cells (ILCs) producing IL-22 and/or IL-17, designated as ILC3, comprise a heterogeneous subset of cells involved in regulation of gut barrier homeostasis and inflammation. Exogenous environmental cues in conjunction with regulated expression of endogenous factors are key determinants of plasticity of ILC3 toward the type 1 fate. Herein, by using mouse models and transcriptomic approaches, we defined at the molecular level, initial events driving ILC3 expressing natural cytotoxicity receptors (NCR ILC3) to acquire type 1 features. We observed that NCR ILC3 exhibited high basal expression of the signal-dependent transcription factor STAT4 due to T-BET, leading to predisposed potential for the type 1 response. We found that the prototypical inducer of type 3 response, IL-23, played a predominant role over IL-12 by accessing STAT4 and preferentially inducing its phosphorylation in ILC3 expressing T-BET. The early effector program driven by IL-23 was characterized by the expression of IL-22, followed by a production of IFN-γ, which relies on STAT4, T-BET and required chromatin remodeling of the Ifng locus. Altogether, our findings shed light on a feed-forward mechanism involving STAT4 and T-BET that modulates the outcome of IL-23 signaling in ILC3.

JAK/STAT signaling in regulation of innate lymphoid cells: The gods before the guardians

“…Thanks to the coexpression of RORγt and T‐BET, NCR + ILC3 are able to activate both genes typical of the type 3 response and genes associated with the NK cell response, even if the production of IFN‐γ requires a longer kinetics than IL‐22. We also found that selective expression of STAT4 in NCR + ILC3 is involved in amplification of IFN‐γ production in a IL‐23‐dependent manner . Thus, the combinatorial expression of LDTFs and SDTFs can modulate the outcome of cytokine signaling in ILCs.…”

Pleiotropic Role and Bidirectional Immunomodulation of Innate Lymphoid Cells in Cancer

“…Plasticity between ILC3 and ILC1 mediated by IL-23 and also IL-12 produced by CD14 + DC promotes polarization from ILC3s toward ILC1s, which ultimately affects tumor immunosurveillance in response to various environmental changes (2,103,150). IL-23-induced activation of STAT4 in NCR + ILC3s is a key determinant of plasticity from NCR + ILC3s toward ILC1s, as demonstrated by a transcriptomic analysis (157). Moreover, ILC3-to-ILC1 transition was tissue dependent and relied on transcription factor Aiolos and T-bet cooperation to repress regulatory elements active in ILC3s.…”

Innate Lymphoid Cells in Colorectal Cancers: A Double-Edged Sword

“…Finally, LTi are critical for lymphoid organogenesis (49). Beyond this, significant plasticity occurs between ILC subsets depending on environmental stimuli they receive, thus directly impacting on their effector functions and immune responses (50)(51)(52)(53)(54)(55). While ILCs are essential to lymphoid organogenesis and tissue homeostasis, they also participate to the development of autoimmune diseases (56,57) or inflammationdriven carcinogenesis (58) (Figure 1).…”

“…This inflammation can be exacerbated by the loss of barrier protection occurring early during CRC development (93), allowing for the infiltration of microbes and their associated products into the tumor microenvironment. This activates dendritic cells and macrophages to produce IL-23 (94), a key cytokine regulating ILC3 function and plasticity (53,95). Additional stimuli such as IL-12, IL-18, TGF-β, or Notch ligand can profoundly influence ILC3 plasticity (50)(51)(52).…”

“…In the presence of IL-12 or TGF-β, IL-22-expressing ILC3 can acquire ILC1 features and transdifferentiate into IFN-γ producing cells (52). At the molecular level, the transcription factors T-BET, AIOLOS, and Signal Transducer and Activator of Transcription (STAT) 4 induce an ILC1 transcriptional program, repressing in parallel the ILC3 lineage genes (52,53). Transitional ILC3/ILC1 cells were found in human intestinal epithelium (52) and accumulate in inflamed lesions of patients suffering from Crohn's disease (51) suggesting that such plasticity may also occur in inflamed CRC lesions.…”