TCF-1 limits the formation of Tc17 cells via repression of the MAF–RORγt axis

Abstract

Interleukin (IL)-17–producing CD8+ T (Tc17) cells have emerged as key players in host-microbiota interactions, infection, and cancer. The factors that drive their development, in contrast to interferon (IFN)-γ–producing effector CD8+ T cells, are not clear. Here we demonstrate that the transcription factor TCF-1 (Tcf7) regulates CD8+ T cell fate decisions in double-positive (DP) thymocytes through the sequential suppression of MAF and RORγt, in parallel with TCF-1–driven modulation of chromatin state. Ablation of TCF-1 resulted in enhanced Tc17 cell development and exposed a gene set signature to drive tissue repair and lipid metabolism, which was distinct from other CD8+ T cell subsets. IL-17–producing CD8+ T cells isolated from healthy humans were also distinct from CD8+IL-17− T cells and enriched in pathways driven by MAF and RORγt. Overall, our study reveals how TCF-1 exerts central control of T cell differentiation in the thymus by normally repressing Tc17 differentiation and promoting an effector fate outcome.

Polyfunctional, Proinflammatory, Tissue‐Resident Memory Phenotype and Function of Synovial Interleukin‐17A+CD8+ T Cells in Psoriatic Arthritis

“…Genes that were up‐regulated in synovial Tc17 cells compared to Th17 cells included CD8A and CD8B , confirming our gating strategy, plus genes associated with cytolytic activity ( GRZA, GRZB, and PRF1 ) (Figures D and F). Expression levels of TCF7 (encoding T cell factor 1), recently identified as a transcription regulator of mouse Tc17 cells through repression of MAF BZIP transcription factor and retinoic acid receptor–related orphan nuclear receptor γt , were low in synovial Tc17 cells (Supplementary Figure 3C).…”

“…Recent transcriptional analysis of healthy human spleen Tc17 cells revealed a distinct molecular profile compared to IL‐17−CD8+ T cells or Th17 cells . To determine the molecular profile of Tc17 cells from the inflamed PsA joint, we sorted highly pure Tc17, Tc1, and Th17 cells from the SFMCs of patients with PsA for RNA sequencing.…”

“… and ). Recent murine models and transcriptional analysis of healthy human spleen Tc17 cells have shed light on the function of Tc17 cells . However, functional and molecular analysis of human synovial Tc17 cells is essential to elucidate the role of synovial Tc17 cells in PsA/SpA pathogenesis.…”

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

“…Enrichment of the motif trio, T-bet, Runx, and TCF-1, within regions that gain accessibility in the absence of c-Maf suggests that c-Maf also constrains Runx3 and TCF-1 function at suppressed regulatory elements that potentially drive type 1 conversion in WT NKp46 + ILC3s. In support of this notion, TCF-1 promotes the type 1 program in γδ T cells, while counteracting type 17 effector differentiation of Tγδ17, Th17, and Tc17 cells (Yu et al, 2011;Malhotra et al, 2013;Mielke et al, 2019), implying a similar role for TCF-1 in ILC3 plastic conversion. In addition, Runx3 is a cooperative binding partner of T-bet in Th1 gene regulation (Djuretic et al, 2007) and an essential coregulator of T-bet in Th17 cell conversion to an IFNγ + pathogenic state (Wang et al, 2014).…”

Vasoactive intestinal peptide confers anticipatory mucosal immunity by regulating ILC3 activity

“…Mice were given unrestricted access to drinking water containing a mix of ampicillin (1 mg/mL), streptomycin (5 mg/mL) and colistin (1 mg/mL) (Sigma) for two weeks [78][79][80] . Gut decontamination was evaluated by macroscopic evaluation of caecal hypertrophy.…”