c-Maf regulates the plasticity of group 3 innate lymphoid cells by restraining the type 1 program

Abstract

CCR6− group 3 innate lymphoid cells (ILC3s) are mediators of intestinal immunity and barrier function that possess the capacity to acquire type 1 effector features and fully convert into ILC1s. The molecular mechanisms governing such plasticity are undefined. Here, we identified c-Maf as an essential regulator of ILC3 homeostasis and plasticity that limits physiological ILC1 conversion. Phenotypic analysis of effector status in Maf-deficient CCR6− ILC3s, coupled with evaluation of global changes in transcriptome, chromatin accessibility, and transcription factor motif enrichment, revealed that c-Maf enforces ILC3 identity. c-Maf promoted ILC3 accessibility and supported RORγt activity and expression of type 3 effector genes. Conversely, c-Maf antagonized type 1 programming, largely through restraint of T-bet expression and function. Mapping of the dynamic changes in chromatin landscape accompanying CCR6− ILC3 development and ILC1 conversion solidified c-Maf as a gatekeeper of type 1 regulatory transformation and a controller of ILC3 fate.

c-MAF, a Swiss Army Knife for Tolerance in Lymphocytes

“…Moreover, c-Maf indirectly sustains ILC3 identity by inducing CD127 expression, which strengthens the IL-7-dependent promotion of RORγt expression in ILCs (17). In turn, c-Maf directly represses ILC1 conversion by binding to the Tbx21 locus and inhibiting T-bet expression, and by restraining the type 1 chromatin accessibility landscape (17). Interestingly, this direct binding of c-Maf at the Tbx21 locus was not observed in Th1 cells and seems to be ILC-specific (67).…”

“…They play a crucial role in maintaining epithelial barrier integrity by expressing large amounts of IL-22 and IL-17A (115). While c-Maf has been shown to be expressed early in ILC specification (116), it is preferentially expressed in intestinal ILC3s, particularly in CCR6 − NKp46 + cells (17,117).…”

“…Recent analysis of ILC transcriptional regulatory networks showed that c-Maf regulates the ILC3/ILC1 balance in the intestine (18). c-Maf directly promotes ILC3 identity by upregulating canonical type 3 c-Maf signature genes, common to NKp46 + ILC3s, CCR6 + ILC3s, IL-17-producing γδ T cells, and RORγt + Tregs (17). Moreover, c-Maf indirectly sustains ILC3 identity by inducing CD127 expression, which strengthens the IL-7-dependent promotion of RORγt expression in ILCs (17).…”

“…c-Maf directly promotes ILC3 identity by upregulating canonical type 3 c-Maf signature genes, common to NKp46 + ILC3s, CCR6 + ILC3s, IL-17-producing γδ T cells, and RORγt + Tregs (17). Moreover, c-Maf indirectly sustains ILC3 identity by inducing CD127 expression, which strengthens the IL-7-dependent promotion of RORγt expression in ILCs (17). In turn, c-Maf directly represses ILC1 conversion by binding to the Tbx21 locus and inhibiting T-bet expression, and by restraining the type 1 chromatin accessibility landscape (17).…”

“…Similar to its function in tissue development, the role attributed to c-Maf within immune regulation broadened over the years and has extended to most, if not all, known immune cell types. While the role of c-Maf has also been studied within innate immune cell types (17)(18)(19) and B lymphocytes (20), we focus on c-Maf within T cell subsets, where c-Maf regulates the differentiation as well as the function of multiple subsets of CD4 T cells, lending it a crucial position in T cell immunity. Recent research has revealed the role of c-Maf in the control of intestinal Th17 responses by regulatory T cells, positioning it as an essential factor in regulatory T cell specification and, more broadly, the maintenance of intestinal homeostasis.…”