Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 216, Issue 4, Pages 847-866Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20182010
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Funding
- Carver College of Medicine/Holden Comprehensive Cancer Center, University of Iowa
- Iowa City Veteran's Administration Medical Center
- National Center for Research Resources of the National Institutes of Health [1S10 OD016199]
- National Institutes of Health [AI112579, AI121080, AI139874]
- Veterans Affairs Office of Research and Development Merit Review Program [BX002903A]
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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 lzumo1r. 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.
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