<scp>FCRL</scp>3 promotes <scp>TLR</scp>9‐induced <scp>B</scp>‐cell activation and suppresses plasma cell differentiation

Abstract

F c receptor‐like ( FCRL ) molecules are preferentially expressed by B lymphocytes and possess tyrosine‐based immunoregulatory function. Although they generally inhibit B ‐cell receptor signaling, their influence on other activation pathways remains largely unexplored. In humans, FCRL 3 encodes a type I transmembrane protein harboring both cytoplasmic ITAM and ITIM elements that can repress B ‐cell receptor activation. Despite this inhibitory property, mounting associations for FCRL 3 with autoimmune and lympho‐proliferative disorders imply a role for it in promoting B ‐cell pathogenesis. Here, we explore the influence of FCRL3 on B ‐cell responses to innate TLR 9 stimulation. A detailed survey of blood B ‐cell populations found that FCRL 3 expression increased as a function of differentiation and was higher among memory subsets with innate‐like features. FCRL 3 ligation augmented C p G oligodeoxynucleotide TLR 9‐mediated B ‐cell proliferation, activation, and survival, but surprisingly, abrogated plasma cell differentiation and antibody production. Although FCRL 3 amplified the NF ‐κ B and mitogen‐activated protein kinase signaling cascades, it halted C p G triggered BLIMP 1 induction in an ERK ‐dependent fashion. These findings indicate that FCRL 3 differentially modulates innate signaling in B cells and provide new insight into the potential of this disease‐associated receptor to counter‐regulate adaptive and innate immunity.