TY - JOUR
T1 - B cells drive autoimmunity in mice with CD28-deficient regulatory T cells
AU - Zhang, Ruan
AU - Sage, Peter T.
AU - Finn, Kelsey
AU - Huynh, Alexandria
AU - Blazar, Bruce R.
AU - Marangoni, Francesco
AU - Mempel, Thorsten R.
AU - Sharpe, Arlene H.
AU - Turka, Laurence A.
N1 - 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.
PY - 2017/12/15
Y1 - 2017/12/15
N2 - 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.
AB - 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.
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U2 - 10.4049/jimmunol.1700409
DO - 10.4049/jimmunol.1700409
M3 - Article
C2 - 29093061
AN - SCOPUS:85038582722
SN - 0022-1767
VL - 199
SP - 3972
EP - 3980
JO - Journal of Immunology
JF - Journal of Immunology
IS - 12
ER -