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

• DOI: 10.1084/jem.20182010
• Publication Date: 2019-03-05T19:35:23Z
• Authors: Shaojun Xing; Kexin Gai; Xiang Li; Peng Shao; Zhouhao Zeng; Xudong Zhao; Xin Zhao; Xia Chen; William J. Paradee; David K. Meyerholz; Weiqun Peng; Hai-Hui Xue
• Keywords: Male; Lymphoid Enhancer-Binding Factor 1; Dextran Sulfate; Cell Differentiation; Mice, Transgenic; CD8-Positive T-Lymphocytes; Colitis; T-Lymphocytes, Regulatory; Mice, Inbred C57BL; Disease Models, Animal; Mice; 03 medical and health sciences; 0302 clinical medicine; Immune Tolerance; Animals; Female; Hepatocyte Nuclear Factor 1-alpha; Transcriptome; Research Articles

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.