B cells drive autoimmunity in mice with CD28-deficient regulatory T cells

Ruan Zhang, Peter T. Sage, Kelsey Finn, Alexandria Huynh, Bruce R. Blazar, Francesco Marangoni, Thorsten R. Mempel, Arlene H. Sharpe, Laurence A. Turka

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


Follicular regulatory T (TFR) cells are a newly defined regulatory T cell (Treg) subset that suppresses follicular helper T cell- mediated B cell responses in the germinal center reaction. The precise costimulatory signal requirements for proper TFR cell differentiation and function are still not known. Using conditional knockout strategies of CD28, we previously demonstrated that loss of CD28 signaling in Tregs caused autoimmunity in mice (termed CD28-DTreg mice), characterized by lymphadenopathy, accumulation of activated T cells, and cell-mediated inflammation of the skin and lung. In this study, we show that CD28 signaling is required for TFR cell differentiation. Treg-specific deletion of CD28 caused a reduction in TFR cell numbers and function, which resulted in increased germinal center B cells and Ab production. Moreover, residual CD28-deficient TFR cells showed a diminished suppressive capacity as assessed by their ability to inhibit Ab responses in vitro. Surprisingly, genetic deletion of B cells in CD28- DTreg mice prevented the development of lymphadenopathy and CD4+ T cell activation, and autoimmunity that mainly targeted skin and lung tissues. Thus, autoimmunity occurring in mice with CD28-deficient Tregs appears to be driven primarily by loss of TFR cell differentiation and function with resulting B cell-driven inflammation.

Original languageEnglish (US)
Pages (from-to)3972-3980
Number of pages9
JournalJournal of Immunology
Issue number12
StatePublished - Dec 15 2017

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health Grants AI-037691, AI 040614, AI-056299, and HL-11879.

Publisher Copyright:
Copyright © 2017 by The American Association of Immunologists, Inc. All rights reserved.


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