Transcriptional regulation of memory B cell differentiation

Abstract

During an immune response, B cells that encounter their cognate antigen become activated and differentiate to form short-lived antibody-secreting cells or germinal centre (GC)-independent memory B cells (MBCs). Within the GC, B cells engage with antigen and compete for limiting amounts of T cell help, which is necessary for B cell survival, proliferation and eventual differentiation into plasma cells or GC-derived MBCs 1. The GC is also the primary site in which B cells undergo somatic hypermutation, with B cells that accrue productive mutations preferentially receiving T cell help. The GC response is required for the development of affinity-matured plasma cells and MBCs (Box 1). MBCs are an important component of protective immunity. MBCs are distinguished by their capacity to survive long term and to rapidly differentiate into antibody-secreting cells upon antigen re-encounter. MBCs can also re-enter the GC during recall responses, where they undergo further somatic hypermutation 2-5. MBCs tend to emerge from the GC during the early phases of the GC response and typically display reduced levels of somatic hypermutation and affinity maturation relative to plasma cells 6-8. In the context of viral infections, the reduced mutational load of MBCs allows these cells to maintain enhanced flexibility in their responsiveness to different viral subtypes compared with plasma cells, which tend to be specific for a particular subtype. Indeed, the MBC population contains an elevated fraction of broadly reactive clones relative to the plasma cell pool for numerous pathogens in both mice and humans 9-12. The MBC response comprises multiple subsets, identified based on their expression of CD80 and PDL2, among other markers 5,8 (Box 2). These MBC subsets emerge from the GC at different times and vary in their capacity to re-enter the GC or differentiate into antibody-secreting cells upon antigen re-encounter 5,6. Iterative exposure to cross-reactive viral antigens is an emerging vaccination strategy designed to elicit broadly reactive MBCs capable of mediating heterosubtypic immunity against pathogens such as influenza. The potential efficacy of an iterative vaccination strategy is limited by the relative inefficiency with which most MBC clones re-enter the GC response 13-15. The secondary GC response tends to consist largely of recently activated naive B cells, with only certain MBC subsets possessing the capacity to efficiently re-enter the GC 4,5,16. Currently, it is unclear why the majority of MBCs fail to participate in secondary GC responses. One possibility is that antigen-specific antibodies limit the ability of MBC clones of the same specificity to access antigen and participate in the GC response 4,17. MBCs can arise through both GC-dependent and GC-independent pathways 18-20. GC-independent MBCs largely develop during the early stages of the immune response and contribute to protective immunity against numerous pathogens including Ehrlichia muris and malaria 14,21. GC-independent MBCs can be somatically hypermutated ...

A single-cell atlas of lymphocyte adaptive immune repertoires and transcriptomes reveals age-related differences in convalescent COVID-19 patients

“…Analysis of BCR repertoires and transcriptomes revealed that the highest levels of SHM and Ig class-switching occurred in the memory B cell subset. This finding is consistent with the generation of germinal center-derived memory B cells following antigen encounter 61,62 . Similarly, SHM and Ig class-switching levels were directly correlated with B cell clonal expansion.…”

Positive Selection in the Light Zone of Germinal Centers

“…A transcription factor, hematopoietically-expressed homeobox protein (Hhex) that is expressed in MBC precursors and promotes MBC differentiation ( 50 , 90 ) can interact with cMyc to decrease its activity, including cell proliferation and metabolism in tumors ( 96 ). Reception of differential signals for positive selection induces these transcription factors at varied levels in positively selected GC-B cells ( 97 ), which most likely play a part in MBC differentiation. However, the overall nature of the signaling network for transition from GC-B cell to MBCs remains unknown.…”

Influenza-specific effector memory B cells predict long-lived antibody responses to vaccination in humans

“…These terminally differentiated effectors, can reduce the duration of infection and decrease morbidity and mortality (Lee et al, 2011). The cues that direct memory B cells toward this early protective effector PB fate and the relationship between effector-like memory B cells and other durable GC-derived or extrafollicular memory B cell populations are not well understood (Laidlaw and Cyster, 2020).…”