Tcf1 and Lef1 are required for the immunosuppressive function of regulatory T cells

Abstract

Tcf1 and Lef1 have versatile functions in regulating T cell development and differentiation, but intrinsic requirements for these factors in regulatory T (T reg) cells remain to be unequivocally defined. Specific ablation of Tcf1 and Lef1 in T reg cells resulted in spontaneous multi-organ autoimmunity that became more evident with age. Tcf1/Lef1-deficient T regs showed reduced protection against experimentally induced colitis, indicative of diminished immuno-suppressive capacity. Transcriptomic analysis revealed that Tcf1 and Lef1 were responsible for positive regulation of a subset of T reg–overrepresented signature genes such as Ikzf4 and Izumo1r. Unexpectedly, Tcf1 and Lef1 were necessary for restraining expression of cytotoxic CD8+ effector T cell–associated genes in T reg cells, including Prdm1 and Ifng. Tcf1 ChIP-seq revealed substantial overlap between Tcf1 and Foxp3 binding peaks in the T reg cell genome, with Tcf1-Foxp3 cooccupancy observed at key T reg signature and cytotoxic effector genes. Our data collectively indicate that Tcf1 and Lef1 are critical for sustaining T reg suppressive functions and preventing loss of self-tolerance.

TCF-1 deficiency influences the composition of intestinal microbiota and enhances susceptibility to colonic inflammation

“…2B and 2C, left panel). In consistent with the previous study (Xing et al, 2019), these results indicated that TCF-1 deficiency leads to enhanced colitis. However, these severe colitis symptoms are not only originated from dysbiosis since the intestinal inflammation is associated with multiple complicated factors.…”

Dynamic changes in the regulatory T-cell heterogeneity and function by murine IL-2 mutein

“…When grouped by resting, primed/activated, and activated Treg subsets, cell states had differential expression of known lymphoid-associated and activated genes. Resting Tregs (C1) have high expression of lymphoid-tissue homing receptors (Ccr7 and S1pr1) and Treg-establishing transcriptional regulators (Lef1 [Xing et al, 2019], Satb1 [Kitagawa et al, 2017], and Klf2 [Pabbisetty et al, 2016]) and low-activation marker expression (Ctla4, Icos, Tnfrsf1b, and Tnfrsf4) ( Figs 3D and S7A), suggesting that they either have not yet undergone TCR-mediated activation or have a central memory-like phenotype.…”

Dynamic changes in the regulatory T cell heterogeneity and function by murine IL-2 mutein

“…Cell states identified by clustering could be grouped into resting, primed/activated, and activated Treg populations based on known lymphoid-associated and activated gene expression. Resting Tregs (C1) have high expression of lymphoid-tissue homing receptors (Ccr7, S1pr1, Sell) and Treg-establishing 5 transcriptional regulators (Lef1 (22), Satb1(23) and Klf2 (24)) and low activation marker expression (Ctla4, Icos, Tnfrsf1b, Tnfrsf4) ( Fig. 2D, Fig.…”