FCRL5+ Memory B Cells Exhibit Robust Recall Responses

Kim, Charles C.; Baccarella, Alyssa; Bayat, Aqieda; Pepper, Marion; Fontana, Mary F.

doi:10.1016/j.celrep.2019.04.019

Cited by 92 publications

(103 citation statements)

References 53 publications

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“…Expansion of atypical MBCs is also associated with progression of autoimmune diseases 79 . Atypical MBCs expand following infection or protein immunization and rapidly differentiate into GC B cells or antibody-secreting cells upon recall 14 , 21 , 153 . Atypical MBCs can be either IgM + or class-switched, with the expression of T-bet important for the development of IgG2a + cells 154 .…”

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confidence: 99%

Transcriptional regulation of memory B cell differentiation

2020

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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 ...

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Transcriptional regulation of memory B cell differentiation

2020

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“…In line with this uncertainty, the expression levels of markers that have been associated with functional deficiency may vary greatly in atMBC from different individuals, supporting the hypothesis that atMBC is a heterogeneous population, probably influenced by the time since antigen exposure. 9 Indeed, atMBC may be recently activated cMBC, 9 which would make them refractory to further activation by antigen or other stimuli. Functional studies addressing whether B-cell stimulation with different SARS-CoV-2 proteins directly causes upregulation of inhibitory pathways in B cells, resulting in accumulation of atMBC that may be unable to neutralize the virus, are currently underway in our laboratory.…”

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Expansion of atypical memory B cells is a prominent feature of COVID-19

et al. 2020

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“…Markedly high FCRL2, FCRL3, and FCRL5 were identified in the context of Hepatitis C vaccination 68 . T-bet and FCRL5+ memory B cells correlate with longevity of antigen-specific antibody responses 69 , however there are conflicting data on longevity and FCRL5+ memory B cells 70 , 71 . We found a weak negative correlation between Tbet and half life in MVA trials (HVTN 094, 205) and no other correlations.…”

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Impact of vaccine type on HIV-1 vaccine elicited antibody durability and B cell gene signature

Palli

Seaton

Piepenbrink

et al. 2020

Sci Rep

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Efficacious HIV-1 vaccination requires elicitation of long-lived antibody responses. However, our understanding of how different vaccine types elicit durable antibody responses is lacking. To assess the impact of vaccine type on antibody responses, we measured IgG isotypes against four consensus HIV antigens from 2 weeks to 10 years post HIV-1 vaccination and used mixed effects models to estimate half-life of responses in four human clinical trials. Compared to protein-boosted regimens, half-lives of gp120-specific antibodies were longer but peak magnitudes were lower in Modified Vaccinia Ankara (MVA)-boosted regimens. Furthermore, gp120-specific B cell transcriptomics from MVA-boosted and protein-boosted vaccines revealed a distinct signature at a peak (2 weeks after last vaccination) including CD19, CD40, and FCRL2-5 activation along with increased B cell receptor signaling. Additional analysis revealed contributions of RIG-I-like receptor pathway and genes such as SMAD5 and IL-32 to antibody durability. Thus, this study provides novel insights into vaccine induced antibody durability and B-cell receptor signaling. While vaccine-elicited antibody durability has been achieved for licensed vaccines such as yellow fever, measles, smallpox, and Hepatitis B, elicitation of long-lived, functional antibody responses with candidate HIV-1 vaccine regimens remains elusive 1,2. In the case of experimental HIV vaccines, efficacy is correlated with Envelope (Env)-specific antibody responses 3,4. In particular, Env IgG3 titers that mediate antibody-dependent cellular phagocytosis (ADCP) and antibody dependent cellullar cytotoxicity (ADCC) are correlated with decreased risk of infection 5,6. However, these responses decay more than 10-fold 6-months post-vaccination, paralleling the decline in vaccine efficacy 7. Estimates of HIV-1 specific IgG half-lives range from 25-213 days, depending on the vaccine regimen and antigen (excluding gp41) 7-9. Interestingly, the Vaccine-Induced HIV Seropositivity/ Reactivity (VISP/VISR) in non-infected HIV vaccine recipients is commonly observed for vaccines with a Gag or Env component 10 , indicating that antibody responses can remain detectable for several weeks to a year postvaccination. However, positive results on diagnostic tests are qualitative in nature and thus not quantitative in

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FCRL5+ Memory B Cells Exhibit Robust Recall Responses

Cited by 92 publications

References 53 publications

Transcriptional regulation of memory B cell differentiation

Transcriptional regulation of memory B cell differentiation

Expansion of atypical memory B cells is a prominent feature of COVID-19

Impact of vaccine type on HIV-1 vaccine elicited antibody durability and B cell gene signature

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