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

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.

Engineered B cells expressing an anti-HIV antibody enable memory retention, isotype switching and clonal expansion

“…CD40 ligation can produce germinal center (GC)-like B cells and antibody secreting plasma cells ex vivo 16 . However, B cells activated ex vivo through CD40 ligation express high levels of CD80, which are associated with a reduced propensity for further activation in vivo upon immunization 17 , 18 . In particular, these cells have a diminished capacity to home to GCs, establish immunological memory and undergo SHM and affinity maturation 10 , 18 .…”

“…However, B cells activated ex vivo through CD40 ligation express high levels of CD80, which are associated with a reduced propensity for further activation in vivo upon immunization 17 , 18 . In particular, these cells have a diminished capacity to home to GCs, establish immunological memory and undergo SHM and affinity maturation 10 , 18 . In contrast, TLR-pathway mediated activation of donor B cells, coming from a transgenic mouse, was recently shown to allow homing to recipient’s GCs upon immunization 9 .…”

Restriction of memory B cell differentiation at the germinal center B cell positive selection stage

“…Genes involved in signal transduction included Itpr1 , a Ca 2+ channel required for normal B cell development and function ( Tang et al, 2017 ); Map2k7 , which directly activates c-JUN and is known to have an antiproliferative activity in B cells ( Sasaki et al, 2001 ; Tournier et al, 1997 ); the AKT substrate Akt1s1 , which negatively regulates mTOR activity ( Sancak et al, 2007 ); and Vav2 , which is critical for humoral immune responses and B cell maturation ( Doody et al, 2001 ). Genes involved in gene expression included Myh9 , which regulates BCR-mediated antigen acquisition and B cell activation ( Hoogeboom et al, 2018 ); and multiple transcription factors, including Bcl11a , which is essential for B cell development and repressed by BLIMP1 during PC differentiation ( Minnich et al, 2016 ; Yu et al, 2012 ); Rela , which was shown to be required for GC-derived PC formation and more recently also for MBC differentiation ( Heise et al, 2014 ; Koike et al, 2019 ); and Mafk , which encodes for the transcription factor MAFK with which BACH2 heterodimerizes to bind target genes in B cells ( Huang et al, 2014 ; Oyake et al, 1996 ). In summary, we found increased expression of multiple MIZ1 target genes in the absence of MYC–MIZ1 complexes.…”

B cell memory: building two walls of protection against pathogens

“…On challenge, CD80 + PDL2 + memory B cells that were of relatively high affinity differentiated into plasma cells but not GC B cells, and conversely CD80 -PDL2memory B cells that were of lower affinity produced few plasma cells but robustly differentiated into GC B cells. In a separate study, CD80 hi memory B cells were shown to be generated from high-affinity B cells during the primary immune response by mechanisms that depended on T FH cell-inducing strong CD40 signalling in contrast to the development CD80 low B cells, which did not require strong CD40 signalling 74 .…”