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Protection against pathogen re-infection is mediated, in large part, by two humoral cellular compartments, namely, long-lived plasma cells and memory B cells. Recent data have reinforced the importance of memory B cells, particularly in response to re-infection of different viral subtypes or in response with viral escape mutants. In regard to memory B cell generation, considerable advancements have been made in recent years in elucidating its basic mechanism, which seems to well explain why the memory B cells pool can deal with variant viruses. Despite such progress, efforts to develop vaccines that induce broadly protective memory B cells to fight against rapidly mutating pathogens such as influenza virus and HIV have not yet been successful. Here, we discuss recent advances regarding the key signals and factors regulating germinal center-derived memory B cell development and activation and highlight the challenges for successful vaccine development.

There is increasing evidence that lung-resident memory T and B cells play a critical role in protecting against respiratory reinfection. With a unique transcriptional and phenotypic profile, resident memory lymphocytes are maintained in a quiescent state, constantly surveying the lung for microbial intruders. Upon reactivation with cognate antigen, these cells provide rapid effector function to enhance immunity and prevent infection. Immunization strategies designed to induce their formation, alongside novel techniques enabling their detection, have the potential to accelerate and transform vaccine development. Despite most data originating from murine studies, this review will discuss recent insights into the generation, maintenance and characterisation of pulmonary resident memory lymphocytes in the context of respiratory infection and vaccination using recent findings from human and non-human primate studies.

B cells secrete antibodies and mediate the humoral immune response, making them extremely important in protective immunity against SARS-CoV-2, which caused the coronavirus disease 2019 (COVID-19) pandemic. In this review, we summarize the positive function and pathological response of B cells in SARS-CoV-2 infection and re-infection. Then, we structure the immunity responses that B cells mediated in peripheral tissues. Furthermore, we discuss the role of B cells during vaccination including the effectiveness of antibodies and memory B cells, viral evolution mechanisms, and future vaccine development. This review might help medical workers and researchers to have a better understanding of the interaction between B cells and SARS-CoV-2 and broaden their vision for future investigations.

The formation of B cell immunological memory happens after the first encounter with a pathogen. At the germinal center (GC), B cells experience complex transcriptional and epigenetic transitions to differentiate into memory B cells (MBCs) and plasma cells (PCs). In particular, the differentiation of GC B cells into MBCs has been poorly understood, and no clear conclusions on the signals and transcription factors leading to this cell fate have been identified. Recent discoveries in epigenetics and immune memory have elucidated the essential role of epigenetic regulators in establishing the memory B cell (MBC) fate. DNA methylation regulators, histone modifiers, noncoding RNAs (ncRNAs), and chromatin remodelers orchestrate a dynamic reprograming of the MBC phenotype. Positive and negative epigenetic regulators of the B cell program collaborate at each differentiation stage and allow for complex chromatin topology rearrangements and dynamic exposure to transcription and translation. Following MBC fate determination at the GC, the acquired epigenetic modifications induce a poised regulatory state where genes are epigenetically marked to remain transcriptionally inactive, but primed for rapid activation upon stimuli. Thus, a poised epigenetic control over gene expression governs MBC formation and a novel model of epigenetic reprograming is proposed. This model provides a novel perspective on how the B cell fate is determined in the GC and memory is formed, offering insights for improved vaccination and therapeutical approaches.

Tuberculosis (TB) is a major global health problem and the only currently-licensed vaccine, BCG, is inadequate. Many TB vaccine candidates are designed to be given as a boost to BCG; an understanding of the BCG-induced immune response is therefore critical, and the opportunity to relate this to circumstances where BCG does confer protection may direct the design of more efficacious vaccines. While the T cell response to BCG vaccination has been well-characterized, there is a paucity of literature on the humoral response. We demonstrate BCG vaccine-mediated induction of specific antibodies in different human populations and macaque species which represent important preclinical models for TB vaccine development. We observe a strong correlation between antibody titers in serum versus plasma with modestly higher titers in serum. We also report for the first time the rapid and transient induction of antibody-secreting plasmablasts following BCG vaccination, together with a robust and durable memory B cell response in humans. Finally, we demonstrate a functional role for BCG vaccine-induced specific antibodies in opsonizing mycobacteria and enhancing macrophage phagocytosis in vitro , which may contribute to the BCG vaccine-mediated control of mycobacterial growth observed. Taken together, our findings indicate that the humoral immune response in the context of BCG vaccination merits further attention to determine whether TB vaccine candidates could benefit from the induction of humoral as well as cellular immunity.

In total, this study provides insights into the multifaceted role of unswitched memory B cells during viral infection. Since many different types of B cells exist in homeostasis, arise in response to infection, or develop along with autoimmunity and strategies used in the field to identify subsets can be heterogeneous,Pernes et al.caution against using surface markers alone to profile B cell subsets. [...]this editor believes that development of technology that can link protein & gene expression with cellular function will ultimately provide the best advantage to shedding light on the complex nature of unswitched memory B cells in human health and disease. Conflict of interest The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Recent clinical studies suggest that more potent B cell depleting therapies and targeting more than one B cell antigen may result in improved clinical responses in autoimmune diseases and hematological malignancies. Here we describe an anti-CD19/CD20 bispecific antibody, HB2198, generated using GEM-DIMER™ technology. HB2198 incorporates Fab domains from rituximab and humanized FMC63 (huFMC63) for bivalent binding of both CD19 and CD20 and comprises two enhanced Fc domains to enable powerful effector functions via bivalent binding of Fcγ receptors (FcγR). Enhanced bivalent binding of HB2198 to FcγR was confirmed in vitro. HB2198 demonstrated robust depletion of human B cells that exceeded the levels observed with comparator anti-CD19 or anti-CD20 IgG1 antibodies in vitro. The mechanism of action of HB2198 included enhanced antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), as well as complement-dependent cytotoxicity (CDC) and direct cell killing activity. In cynomolgus monkeys, HB2198 administration resulted in > 99% depletion of circulating B cells within 1–3 days and mediated a durable shift in proportions of naïve and memory B cells in vivo. These data support the conclusion that HB2198 may provide an improved treatment option when potent and broad depletion of both CD19 + and CD20 + cells is required.

Epstein-Barr virus (EBV) is a ubiquitous human pathogen, infecting up to 95% of the world’s adult population. Initial infection with EBV can cause infectious mononucleosis. The innate immune system serves as frontline defense against pathogens, such as bacteria and viruses. Natural killer (NK) cells are a part of innate immunity and can both secrete cytokines and directly target cells for lysis. NK cells express several cell surface receptors, including NKG2D, which bind multiple ligands. People with deficiencies in NK cells are often susceptible to uncontrolled infection by herpesviruses, such as Epstein-Barr virus (EBV). Infection with EBV stimulates both innate and adaptive immunity, yet the virus establishes lifelong latent infection in memory B cells. We show that the EBV oncogene EBNA1, previously known to be necessary for maintaining EBV genomes in latently infected cells, also plays an important role in suppressing NK cell responses and cell death in newly infected cells. EBNA1 does so by downregulating the NKG2D ligands ULBP1 and ULBP5 and modulating expression of c-Myc. B cells infected with a derivative of EBV that lacks EBNA1 are more susceptible to NK cell-mediated killing and show increased levels of apoptosis. Thus, EBNA1 performs a previously unappreciated role in reducing immune response and programmed cell death after EBV infection, helping infected cells avoid immune surveillance and apoptosis and thus persist for the lifetime of the host. IMPORTANCE Epstein-Barr virus (EBV) is a ubiquitous human pathogen, infecting up to 95% of the world’s adult population. Initial infection with EBV can cause infectious mononucleosis. EBV is also linked to several human malignancies, including lymphomas and carcinomas. Although infection by EBV alerts the immune system and causes an immune response, the virus persists for life in memory B cells. We show that the EBV protein EBNA1 can downregulate several components of the innate immune system linked to natural killer (NK) cells. This downregulation of NK cell activity translates to lower killing of EBV-infected cells and is likely one way that EBV escapes immune surveillance after infection. Additionally, we show that EBNA1 reduces apoptosis in newly infected B cells, allowing more of these cells to survive. Taken together, our findings uncover new functions of EBNA1 and provide insights into viral strategies to survive the initial immune response postinfection.

Affinity maturation and differentiation of B cells in the germinal center (GC) are tightly controlled by epigenetically regulated transcription programs, but the underlying mechanisms are only partially understood. Here we show that Cfp1 , an integral component of the histone methyltransferase complex Setd1A/B, is critically required for GC responses. Cfp1 deficiency in activated B cells greatly impairs GC formation with diminished proliferation, somatic hypermutation and affinity maturation. Mechanistically, Cfp1 deletion reduces H3K4me3 marks at a subset of cell cycle and GC-related genes and impairs their transcription. Importantly, Cfp1 promotes the expression of transcription factors MEF2B and OCA-B and the Bcl6 enhancer-promoter looping for its efficient induction. Accordingly, Cfp1 -deficient GCB cells upregulate IRF4 and preferentially differentiate into plasmablasts. Furthermore, Cfp1 ablation upregulates a panel of pre-memory genes with elevated H3K4me3 and leads to markedly expanded memory B populations. In summary, our study reveals that Cfp1 -safeguarded epigenetic regulation ensures proper dynamics of GCB cells for affinity maturation and prevents the pre-mature exit from GC as memory cells. Cellular differentiation decisions, such as fates of B cells following entry into the germinal centres, are governed by epigenetically and transcriptionally regulated paths for bifurcating cell fates. Here the authors show that CFP1 is a master epigenetic regulator of activated B cells and controls their hypermutation and affinity maturation via the histone methyltransferase complex Setd1A/B.

Belimumab, a fully humanized B cell-activating factor (BAFF)-targeting monoclonal antibody, inhibits autoreactive B cell survival and improves systemic lupus erythematosus (SLE) clinical outcomes. However, its administration criteria remain unclear. To establish a basis for defining these criteria, we characterized the immune cell subpopulation alterations post-belimumab treatment and elucidated the underlying mechanisms. We hypothesized that belimumab modulates specific cell subsets and investigated the post-therapy changes. Flow cytometry and correlation analysis revealed that the frequency of B- and T-lymphocyte attenuator (BTLA)high memory B cells in peripheral blood and clinical improvement after belimumab treatment. Western blotting analysis of healthy control B cells revealed that BTLA engagement suppressed Bruton tyrosine kinase and phospholipase C-gamma 2 phosphorylation, which was enhanced by B cell and BAFF receptor co-stimulation. BTLA-expressing memory B cells, which positively correlate with disease improvement, possibly contributed to SLE improvement via BTLA-mediated signaling that attenuated B cell- and BAFF receptor-induced intracellular pathways. To validate these findings, we plan to further assess the effects of belimumab on BTLA expression and B cell signaling pathways in treatment-naive patients with SLE by western blotting. Collectively, our results provide a novel foundation for establish appropriate belimumab administration criteria.