T Follicular Regulatory Cell–Derived Fibrinogen-like Protein 2 Regulates Production of Autoantibodies and Induction of Systemic Autoimmunity
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; Regev, Aviv; Wang, Chao; Yosef, Nir; Kuchroo, Vijay K; ... Show more Show less
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© 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.
Journal of immunology
The American Association of Immunologists
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).
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