The C5aR2 pathway as a potential novel checkpoint for B cell activation and differentiation
SCHANZENBACHER J. 1, KÖHL J. 1,2, KARSTEN C. 1
1 Institute of Systemic Inflammation Research (ISEF), University of Lübeck, Lübeck, Germany; 2 Division of Immunobiology, Cincinnati Childrens Hospital Medical Center, University of Cincinnati College of Medicine , Cincinnati, Oh, United States
Complement C5a has been shown to be critically involved in many autoimmune diseases through activation of its cognate receptors, C5aR1 and C5aR2, expressed on effector cells. While the role of C5aR1 in autoimmune disease is well understood, the function of C5aR2 remains elusive. Initially thought to be a decoy receptor that negatively regulates the functions of C5aR1, C5aR2 has recently been shown to exert both pro- and anti-inflammatory properties independent of C5aR1. Recent experiments by our group using C5aR2 reporter mice showed that B cells express C5aR2 but not C5aR1 in the steady state. We also observed an altered maturation of B cells in C5ar2–/– mice. These findings prompted us to further investigate the role of C5aR2 in B cells. First, assessing the role of C5aR2 for B cells under homeostatic conditions, we found that naive splenic B cells from C5ar2–/– mice showed a drastically increased expression of the decay accelerating factor (DAF) compared to B cells from wild-type and C5ar1–/– mice. Since the regulation of DAF expression has been shown to be critical for a functional germinal centre response, we hypothesised that the increased DAF expression in B cells of C5ar2–/– mice might affect their differentiation. To investigate this, we used an in vitro culture system in which we co-cultured splenic B cells with 40LB fibroblast feeder cells that exogenously express CD40?ligand (CD40L) and B cell activating factor (BAFF), which promote B cell proliferation and survival and mimic the germinal center response. Flow cytometric analysis of the co-cultured B cells revealed attenuated activation, differentiation and class switching of B cells from C5ar2–/– mice compared to the wild-type. Taken together, our findings highlight a potential role of C5aR2 as a novel checkpoint for B cell development, possibly by regulating DAF expression during B cell maturation.