T Follicular Regulatory Cell–Derived Fibrinogen-like Protein 2 Regulates Production of Autoantibodies and Induction of Systemic Autoimmunity
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nihms-1640337.pdf
Description
Accepted version
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3.26 MB
Format
Adobe PDF
Checksum (MD5)
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Author(s)
Sungnak, Waradon
Wagner, Allon
Kowalczyk, Monika S
Bod, Lloyd
Kye, Yoon-Chul
Sage, Peter T
Sharpe, Arlene H
Sobel, Raymond A
Quintana, Francisco J
Rozenblatt-Rosen, Orit
Date Issued
2020
Journal
Journal of immunology
Publisher
The American Association of Immunologists
Citation
Sungnak, Waradon, Wagner, Allon, Kowalczyk, Monika S, Bod, Lloyd, Kye, Yoon-Chul et al. 2020. "T Follicular Regulatory Cell–Derived Fibrinogen-like Protein 2 Regulates Production of Autoantibodies and Induction of Systemic Autoimmunity." Journal of immunology, 205 (12).
Version
Author's final manuscript
Abstract
© 2020 by The American Association of Immunologists, Inc. T follicular regulatory (TFR) cells limit Ab responses, but the underlying mechanisms remain largely unknown. In this study, we identify Fgl2 as a soluble TFR cell effector molecule through single-cell gene expression profiling. Highly expressed by TFR cells, Fgl2 directly binds to B cells, especially light-zone germinal center B cells, as well as to T follicular helper (TFH) cells, and directly regulates B cells and TFH in a context-dependent and type 2 Ab isotype-specific manner. In TFH cells, Fgl2 induces the expression of Prdm1 and a panel of checkpoint molecules, including PD1, TIM3, LAG3, and TIGIT, resulting in TFH cell dysfunction. Mice deficient in Fgl2 had dysregulated Ab responses at steady-state and upon immunization. In addition, loss of Fgl2 results in expansion of autoreactive B cells upon immunization. Consistent with this observation, aged Fgl2-/- mice spontaneously developed autoimmunity associated with elevated autoantibodies. Thus, Fgl2 is a TFR cell effector molecule that regulates humoral immunity and limits systemic autoimmunity.
MIT Department
Massachusetts Institute of Technology. Department of Biology
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DOI of Published Version
https://doi.org/10.4049/JIMMUNOL.2000748
