FCRL5 promotes T cell-independent innate-like B cell responses and counter-regulates tolerance through the Lyn/SHP-1 circuit (IRM8P.717)

Abstract The earliest phases of humoral defense are orchestrated by splenic marginal zone (MZ) and body cavity-derived B1 B cells. These frontline responders have been termed “innate-like” given their broadly-reactive natural antibody repertoires and capacity for rapid responses to T cell-independent (TI) antigens. Despite their key contributions to primary responses, why these cells possess such prompt responsivity to innate-stimulation is poorly understood. The discovery of a family of Fc receptor-like (FCRL) molecules with homology to the classical FCRs for IgG and IgE, complex tyrosine-based function, and preferential B cell expression has introduced a new level of humoral regulation. Although their in vivo functions have not yet been investigated, human FCRL (hFCRL) members are becoming increasingly appreciated for their associations with immune-related diseases. In particular, hFCRL3 has emerged as a generalized risk factor in autoimmunity. To better understand the role of hFCRL3 in B cells, we investigated its closest relative mouse FCRL5 (mFCRL5). This molecule shares homologous extracellular domains, binary tyrosine-based signaling, and innate-like B cell expression. Here we demonstrate that Fcrl5 deficiency impairs humoral responses to TI antigens and differentially modulates autoimmunity in lupus-prone SHP-1 and Lyn mutant mice. These data indicate a critical role for mFCRL5 in regulating innate-like B cell function at the interface of host defense and tolerance.