The quantity of CD40 signaling determines the differentiation of B cells into functionally distinct memory cell subsets.

Takuya Koike,Shu Horiuchi,Daisuke Kitamura,Koshi Harada

doi:10.7554/elife.44245

Abstract

In mice, memory B (Bmem) cells can be divided into two subpopulations: CD80hi Bmem cells, which preferentially differentiate into plasma cells; and CD80lo Bmem cells, which become germinal center (GC) B cells during a recall response. We demonstrate that these distinct responses can be B-cell-intrinsic and essentially independent of B-cell receptor (BCR) isotypes. Furthermore, we find that the development of CD80hi Bmem cells in the primary immune response requires follicular helper T cells, a relatively strong CD40 signal and a high-affinity BCR on B cells, whereas the development of CD80lo Bmem cells does not. Quantitative differences in CD40 stimulation were enough to recapitulate the distinct B cell fate decisions in an in vitro culture system. The quantity of CD40 signaling appears to be translated into NF-κB activation, followed by BATF upregulation that promotes Bmem cell differentiation from GC B cells.

Highlights

Memory B (Bmem) cells are crucial for humoral immunity, preventing the spread of re-infecting viruses and bacteria by rapidly producing large amounts of class-switched antibodies (Abs) against these pathogens
On the basis of previous reports showing that IgG1+ Bmem cells are mainly composed of CD80+ PDL2+ and CD80– PD-L2+ Bmem cells and that CD80– PD-L2+ and CD80– PD-L2– Bmem cells are functionally similar (He et al, 2017; Zuccarino-Catania et al, 2014), we hypothesized that the proposed Bmem cell subsets could be distinguished by the expression of CD80, as CD80hi or CD80lo Bmem cells
In order to examine in vitro whether the CD80hi and CD80lo Bmem cells are intrinsically biased in their differentiation fate toward plasma cell (PC) or germinal center (GC) B cells, we transferred into B6 mice allotypically marked (CD45.1+) B cells of B1-8 knock-in mice, whose knock-in IgH chain, when combined with the lL

Summary

Introduction

Memory B (Bmem) cells are crucial for humoral immunity, preventing the spread of re-infecting viruses and bacteria by rapidly producing large amounts of class-switched antibodies (Abs) against these pathogens. The relatively long cytoplasmic tail of mIgG, as compared to that of membrane-bound IgM (mIgM) which consists of only three amino acids, contains specific motifs that recruit signaling molecules such as Grb and SAP97 after BCR cross-linking; these motifs and molecules are required for enhanced BCR signaling and plasma cell (PC) formation upon rechallenge (Engels et al, 2009; Kaisho et al, 1997; Liu et al, 2012; Lutz et al, 2015) At odds with this model is the finding that naıve B cells expressing NP-specific mIgG1, which were derived from cloned mice generated from a single IgG1+ Bmem cell, expanded to a similar extent as NP-specific (IgH-knock-in) IgM+ naıve B cells, and both B cell types predominantly differentiated into GC B cells rather than PCs upon primary immunization (Kometani et al, 2013). In support of this notion, human Bmem cells differentiate into PCs better than do naıve B cells in antigen-free in vitro cultures (Arpin et al, 1997)

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