FoxP3 and Ezh2 regulate Tfr cell suppressive function and transcriptional program

Shenda Hou, Rachel L. Clement, Alos Diallo, Bruce R. Blazar, Alexander Y. Rudensky, Arlene H. Sharpe, Peter T. Sage

Research output: Contribution to journalArticlepeer-review

49 Scopus citations


Follicular regulatory T (Tfr) cells are a regulatory T cell subset that controls antibody production by inhibiting T follicular helper (Tfh)–mediated help to B cells. Tfh and Tfr cells possess opposing functions suggesting unique programming. Here we elucidated the transcriptional program controlling Tfr suppressive function. We found that Tfr cells have a program for suppressive function fine-tuned by tissue microenvironment. The transcription factor FoxP3 and chromatin-modifying enzyme EZH2 are essential for this transcriptional program but regulate the program in distinct ways. FoxP3 modifies the Tfh program to induce a Tfr-like functional state, demonstrating that Tfr cells coopt the Tfh program for suppression. Importantly, we identified a Tfr cell population that loses the Tfr program to become “ex-Tfr” cells with altered functionality. These dysfunctional ex-Tfr cells may have roles in modulating pathogenic antibody responses. Taken together, our studies reveal mechanisms controlling the Tfr transcriptional program and how failure of these mechanisms leads to dysfunctional Tfr cells.

Original languageEnglish (US)
Pages (from-to)605-620
Number of pages16
JournalJournal of Experimental Medicine
Issue number3
StatePublished - Mar 1 2019

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health through grants R01AI40614 (A.H. Sharpe), P01AI56299 (A.H. Sharpe), R01 HL11879 (B.R. Blazar), and K22AI132937 (P.T. Sage) and the Evergrande Center for Immunological Diseases. The authors declare no competing financial interests.

Publisher Copyright:
© 2019 Hou et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at


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