Fibrinogen-like protein 2 (Fgl2) is a critical immunoregulatory factor, yet its precise roles in B-cell biology and mucosal immunity remain largely undefined. In this study, utilizing Fgl2-knockout (KO) mice, we identified novel B cell subsets in the spleen (SPL), predominantly characterized by IGHA clonal dominance. Employing an intestinal Trichinella spiralis (T. s) infection model and samples from patients exhibiting mucosal immune responses (the early stage of COVID-19 infection), we investigated the function of Fgl2 in mucosal immunity. We demonstrate that Fgl2 directly interacts with Receptor for activated C-kinase 1 (Rack1), thereby attenuating B cell receptor (BCR) signaling and metabolic activity by inhibiting AKT phosphorylation. Furthermore, the Fgl2 deficiency-induced expansion of marginal zone (MZ) B cells, germinal center (GC) B cells, and IgA+ plasma cells was effectively counteracted by in vivo Rack1 inhibition. Consistently, a Rack1 inhibitor also abrogated the enhanced activation of Fgl2-deficient B cells in vitro. Fgl2 deficiency also augmented early B cell activation, including B cell spreading, clustering, and signalosome recruitment, through upregulation of the DOCK8-WASP-actin axis. Our research uncovers an intrinsic role for Fgl2 in regulating BCR signaling, B cell differentiation, and mucosal immunity, elucidating a key underlying molecular mechanism.
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