The liver-secreted protein FGL1 restrains a subset of innate-like B cell responses via the receptor TACI.

The liver-secreted protein fibrinogen-like protein 1 (FGL1) is a ligand of the coinhibitory receptor LAG3 on T cells; however, Fgl1-/- mice exhibit autoimmune features distinct from those of Lag3-/- mice. Here, we examined whether FGL1 acts via receptors beyond LAG3 to regulate autoimmunity. Recombinant FGL1 administration reduced autoimmune symptoms in B6/lpr lupus-like mice. This was associated with diminished antigen-specific IgM responses and B cell numbers. Genome-wide surface proteome screening identified the tumor necrosis factor receptor (TNFR) family member transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), a receptor for B cell-activating receptors BAFF and APRIL, as a receptor for FGL1. TACI bound FGL1 via an N-terminal site not required for BAFF and APRIL interaction. The impact of FGL1 administration on B cell numbers and autoimmune phenotypes was lost in Taci-/- mice. Mechanistically, FGL1 promotes TACI internalization, thereby regulating receptor availability for activating ligands. Thus, FGL1 regulates an innate-like subset of B cells via modulating TACI availability, with implications for autoimmunity and inflammation.