FCRL5 regulates innate-like B cell natural antibody production and T cell-independent responses (IRM10P.607)

Abstract

Abstract At homeostasis and during primary responses to pathogens, humoral host defense is chiefly coordinated by body cavity-derived B-1 and splenic marginal zone (MZ) B cells. These early responders have been termed “innate-like” due to their broadly-reactive natural antibody repertoires and rapid responses to T cell-independent (TI) antigens. However, what regulates these functions in these specialized cells remains unclear. Fc receptor-like (FCRL) molecules have homology to the classical FCRs for IgG and IgE, exhibit complex tyrosine-based regulation, and are preferentially expressed by B cells. Notably, these receptor-genes have been increasingly associated with immune disorders and human (h) FCRL3 has emerged as a risk factor in autoimmunity. To better understand hFCRL3’s role in B cells, we investigated its closest relative, mouse FCRL5 (mFCRL5), which shares homologous extracellular domains, binary tyrosine-based signaling, and innate-like B cell expression. Here we characterize the first in vivo model of FCRL function by examining Fcrl5 deficient mice. Our findings demonstrate that at homeostasis Fcrl5 deficient mice have normal total B cell numbers and subset frequencies, but enhanced natural antibody production. By contrast, Fcrl5 deficiency was found to impair TI humoral responses, but T cell-dependent responses remained intact. These data indicate a critical role for mFCRL5 in regulating innate-like B cell function at the interface of host defense and tolerance.