FCRL regulation in innate-like B cells

Abstract

Coelomic cavity-derived B-1 and splenic marginal zone (MZ) B lymphocytes play principal roles in frontline host protection at homeostasis and during primary humoral immune responses. Although they share many features that enable rapid and broad-based defense against pathogens, these innate-like subsets have disparate B cell receptor (BCR) signaling features. Members of the Fc receptor-like (FCRL) family are preferentially expressed by B cells and possess tyrosine-based immunoregulatory function. An unusual characteristic of many of these cell surface proteins is the presence of both inhibitory (ITIM) and activating (ITAM-like) motifs in their cytoplasmic tails. In mice, FCRL5 is a discrete marker of splenic MZ and peritoneal B-1 B cells and has both ITIM and ITAM-like sequences. Recent work explored its signaling properties and identified that FCRL5 differentially influences innate-like BCR function. Closer scrutiny of these differences disclosed the ability of FCRL5 to counter-regulate BCR activation by recruiting SHP-1 and Lyn to its cytoplasmic motifs. Furthermore, the disparity in FCRL5 regulation between MZ and B-1 B cells correlated with relative intracellular concentrations of SHP-1. These findings validate and extend our understanding of the unique signaling features in innate-like B cells and provide new insight into the complexity of FCRL modulation.

Keywords: B cells; BCR signaling; kinase; phosphatase; regulation.

Figure 1

Overview of BCR and FCRL5 tyrosine-based signaling in mouse innate-like B cells. FCRL5 is shown in relation to the BCR and its Ig-α and Ig-β ITAM-bearing (green boxes) signaling adaptor subunits. The FCRL5 cytoplasmic tail has both an ITAM-like sequence and a consensus ITIM (red box). Differences in FCRL5 function between the MZ and B-1 B cell subsets directly correlate with their relative intracellular pools of the protein tyrosine phosphatase SHP-1. BCR signaling is robust in splenic MZ B cells, but the comparatively higher SHP-1 levels in these cells enables FCRL5 to inhibit BCR stimulation when the two receptors are cross-linked. In contrast, peritoneal cavity–derived B-1 B cells have more blunted BCR activation and a lower abundance of SHP-1. With the relatively balanced activity of SHP-1 and Lyn in B-1 B cells, FCRL5 has no apparent influence on BCR activation.