The Transcription Factor T-bet Resolves Memory B Cell Subsets with Distinct Tissue Distributions and Antibody Specificities in Mice and Humans

Johnson, John L.; Rosenthal, Rebecca L.; Knox, James J.; Myles, Arpita; Naradikian, Martin S.; Madej, Joanna; Kostiv, Mariya; Rosenfeld, Aaron M.; Meng, Wenzhao; Christensen, Shannon R.; Hensley, Scott E.; Yewdell, Jonathan W.; Canaday, David H.; Zhu, Jinfang; McDermott, Adrian B.; Dori, Yoav; Itkin, Max; Wherry, E. John; Pardi, Norbert; Weissman, Drew; Naji, Ali; Prak, Eline T. Luning; Betts, Michael R.; Cancro, Michael P.

doi:10.1016/j.immuni.2020.03.020

Cited by 160 publications

(242 citation statements)

References 67 publications

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“…Taken together with the identification of S-reactive MBCs in unexposed healthy donors (19), it is likely that S2-reactive MBCs were below the limit of detection in our assays. Most MBCs are resident in lymphoid tissues, except for MBCs against frequently seen immunogenic antigens (for example, the influenza H1 or TTd in this study), and are at very low frequencies in circulation in steady state (24,25).…”

Section: Discussionmentioning

confidence: 80%

S protein-reactive IgG and memory B cell production after human SARS-CoV-2 infection includes broad reactivity to the S2 subunit

Nguyen-Contant

Embong

Kanagaiah

et al. 2020

Preprint

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The high susceptibility of humans to SARS-CoV-2 infection, the cause of COVID-19, reflects the novelty of the virus and limited preexisting B cell immunity. IgG against the SARS-CoV-2 spike (S) protein, which carries the novel receptor binding domain (RBD), is absent or at low levels in unexposed individuals. To better understand the B cell response to SARS-CoV-2 infection, we asked whether virus-reactive memory B cells (MBCs) were present in unexposed subjects and whether MBC generation accompanied virus-specific IgG production in infected subjects. We analyzed sera and PBMCs from non-SARS-CoV-2-exposed healthy donors and COVID-19 convalescent subjects. Serum IgG levels specific for SARS-CoV-2 proteins (S, including the RBD and S2 subunit, and nucleocapsid [N]) and non-SARS-CoV-2 proteins were related to measurements of circulating IgG MBCs. Anti-RBD IgG was absent in unexposed subjects. Most unexposed subjects had anti-S2 IgG and a minority had anti-N IgG, but IgG MBCs with these specificities were not detected, perhaps reflecting low frequencies. Convalescent subjects had high levels of IgG against the RBD, S2, and N, together with large populations of RBD- and S2-reactive IgG MBCs. Notably, IgG titers against the S protein of the human coronavirus OC43 in convalescent subjects were higher than in unexposed subjects and correlated strongly with anti-S2 titers. Our findings indicate cross-reactive B cell responses against the S2 subunit that might enhance broad coronavirus protection. Importantly, our demonstration of MBC induction by SARS-CoV-2 infection suggests that a durable form of B cell immunity is maintained even if circulating antibody levels wane.IMPORTANCERecent rapid worldwide spread of SARS-CoV-2 has established a pandemic of potentially serious disease in the highly susceptible human population. Key questions are whether humans have preexisting immune memory that provides some protection against SARS-CoV-2 and whether SARS-CoV-2 infection generates lasting immune protection against reinfection. Our analysis focused on pre- and post-infection IgG and IgG memory B cells (MBCs) reactive to SARS-CoV-2 proteins. Most importantly, we demonstrate that infection generates both IgG and IgG MBCs against the novel receptor binding domain and the conserved S2 subunit of the SARS-CoV-2 spike protein. Thus, even if antibody levels wane, long-lived MBCs remain to mediate rapid antibody production. Our study also suggests that SARS-CoV-2 infection strengthens preexisting broad coronavirus protection through S2-reactive antibody and MBC formation.

show abstract

Section: Discussionmentioning

confidence: 80%

S protein-reactive IgG and memory B cell production after human SARS-CoV-2 infection includes broad reactivity to the S2 subunit

Nguyen-Contant

Embong

Kanagaiah

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…On the basis of an estimate of 10 to 20 IgG MASCs generated per IgG MBC after in vitro stimulation ( 26 ), our analysis suggests that the frequency of S2-reactive MBCs, if present in unexposed healthy donors, would be <1/10 6 PBMCs. Most MBCs are resident in lymphoid tissues and, except for MBCs against frequently seen immunogenic antigens (for example, the influenza virus H1 or TTd in this study), are at very low frequencies in the circulation in the steady state ( 27 , 28 ).…”

Section: Discussionmentioning

confidence: 85%

S Protein-Reactive IgG and Memory B Cell Production after Human SARS-CoV-2 Infection Includes Broad Reactivity to the S2 Subunit

Nguyen-Contant

Embong

Kanagaiah

et al. 2020

mBio

208

178

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The high susceptibility of humans to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the cause of coronavirus disease 2019 (COVID-19), reflects the novelty of the virus and limited preexisting B cell immunity. IgG against the SARS-CoV-2 spike (S) protein, which carries the novel receptor binding domain (RBD), is absent or at low levels in unexposed individuals. To better understand the B cell response to SARS-CoV-2 infection, we asked whether virus-reactive memory B cells (MBCs) were present in unexposed subjects and whether MBC generation accompanied virus-specific IgG production in infected subjects. We analyzed sera and peripheral blood mononuclear cells (PBMCs) from non-SARS-CoV-2-exposed healthy donors and COVID-19 convalescent subjects. Serum IgG levels specific for SARS-CoV-2 proteins (S, including the RBD and S2 subunit, and nucleocapsid [N]) and non-SARS-CoV-2 proteins were related to measurements of circulating IgG MBC levels. Anti-RBD IgG was absent in unexposed subjects. Most unexposed subjects had anti-S2 IgG, and a minority had anti-N IgG, but IgG MBCs with these specificities were not detected, perhaps reflecting low frequencies. Convalescent subjects had high levels of IgG against the RBD, S2, and N, together with large populations of RBD- and S2-reactive IgG MBCs. Notably, IgG titers against the S protein of the human coronavirus OC43 were higher in convalescent subjects than in unexposed subjects and correlated strongly with anti-S2 titers. Our findings indicate cross-reactive B cell responses against the S2 subunit that might enhance broad coronavirus protection. Importantly, our demonstration of MBC induction by SARS-CoV-2 infection suggests that a durable form of B cell immunity is maintained even if circulating antibody levels wane. IMPORTANCE The recent rapid worldwide spread of SARS-CoV-2 has established a pandemic of potentially serious disease in the highly susceptible human population. Key issues are whether humans have preexisting immune memory that provides some protection against SARS-CoV-2 and whether SARS-CoV-2 infection generates lasting immune protection against reinfection. Our analysis focused on pre- and postinfection IgG and IgG memory B cells (MBCs) reactive to SARS-CoV-2 proteins. Most importantly, we demonstrate that infection generates both IgG and IgG MBCs against the novel receptor binding domain and the conserved S2 subunit of the SARS-CoV-2 spike protein. Thus, even if antibody levels wane, long-lived MBCs remain to mediate rapid antibody production. Our study results also suggest that SARS-CoV-2 infection strengthens preexisting broad coronavirus protection through S2-reactive antibody and MBC formation.

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“…Atypical MBCs can be either IgM + or class-switched, with the expression of T-bet important for the development of IgG2a + cells 154 . T-bet expression also distinguishes MBC subsets with distinct homing and functional properties 155 . The transcription factor MYB represses T-bet expression in B cells 156 .…”

Section: Regulation Of Mbc Differentiationmentioning

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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The Transcription Factor T-bet Resolves Memory B Cell Subsets with Distinct Tissue Distributions and Antibody Specificities in Mice and Humans

Cited by 160 publications

References 67 publications

S protein-reactive IgG and memory B cell production after human SARS-CoV-2 infection includes broad reactivity to the S2 subunit

S protein-reactive IgG and memory B cell production after human SARS-CoV-2 infection includes broad reactivity to the S2 subunit

S Protein-Reactive IgG and Memory B Cell Production after Human SARS-CoV-2 Infection Includes Broad Reactivity to the S2 Subunit

Transcriptional regulation of memory B cell differentiation

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