FCRL4 and FCRL5 expression distinguishes three human memory B cell subsets in tonsils.

Abstract

Abstract FCRL4 and FCRL5 are two members of the human Fc receptor like family with the capacity to regulate antigen receptor signaling. FCRL4 was shown to bind IgA, whereas FCRL5 binds IgG. Although the expression of FCRL4 and FCRL5 on human B cell subsets has each been individually evaluated, no study thus far addressed their potential co-expression. Here we report that three distinct subpopulations of CD38lowIgD-memory B cells exist in human tonsils, one that co-expresses FCRL4 and FCRL5, another that is FCRL5 single-positive, and a third that lacks both proteins. We found that the FCRL5+FCRL4+ subset expresses the highest levels of surface FCRL5, CD11c, FAS, PD-1, CD32, CCR1, CCR5 and CCR6 protein, as well as the lowest levels of LAIR-1 and CD21 among the three memory B cell populations. Furthermore, microarray analysis demonstrated that the three memory B cells subsets each possess distinct gene expression profiles. The FCRL5+FCRL4− memory B subset overexpressed dozens of immunoglobulin variable genes compared to the other two subsets, in addition to the transcription factors XBP1, PRDM1 and IRF4 that drive plasmablast and plasma cell differentiation. These results suggest that the FCRL5+FCRL4− memory B subset is committed to become plasmablast. Using KREC assay we established that the FCRL5+FCRL4+ subset underwent more rounds of cell divisions than the other two subsets. The low number of cell divisions measured in the FCRL5+FCRL4− subset suggests that the cells bypassed the germinal center. The surprising association of FCRL4 and FCRL5 expression with distinct memory B cell subsets could point to the functional role of these FCRL proteins and their immunoglobulin ligands to drive B cell development.