T Follicular Regulatory Cell-Derived Fibrinogen-like Protein 2 Regulates Production of Autoantibodies and Induction of Systemic Autoimmunity

J Immunol. 2020 Dec 15;205(12):3247-3262. doi: 10.4049/jimmunol.2000748. Epub 2020 Nov 9.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibody Formation*
  • Antigens, CD / genetics
  • Antigens, CD / immunology
  • Autoantibodies / immunology*
  • Autoimmune Diseases / genetics
  • Autoimmune Diseases / immunology*
  • B-Lymphocytes / immunology*
  • Fibrinogen / genetics
  • Fibrinogen / immunology*
  • Hepatitis A Virus Cellular Receptor 2 / genetics
  • Hepatitis A Virus Cellular Receptor 2 / immunology
  • Mice
  • Mice, Knockout
  • Programmed Cell Death 1 Receptor / genetics
  • Programmed Cell Death 1 Receptor / immunology
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / immunology
  • T-Lymphocytes, Regulatory / immunology


  • Antigens, CD
  • Autoantibodies
  • CD223 antigen
  • Fgl2 protein, mouse
  • Havcr2 protein, mouse
  • Hepatitis A Virus Cellular Receptor 2
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Receptors, Immunologic
  • T cell Ig and ITIM domain protein, mouse
  • Fibrinogen