Memory B cell diversity: insights for optimized vaccine design
2022; Elsevier BV; Volume: 43; Issue: 5 Linguagem: Inglês
10.1016/j.it.2022.03.005
ISSN1471-4981
AutoresJoshua J.C. McGrath, Lei Li, Patrick C. Wilson,
Tópico(s)Immunodeficiency and Autoimmune Disorders
ResumoWe hypothesize that circulatory memory B cell (MBC) subphenotypes with specific origins/subfunctions may correlate with the efficacy/durability of existing vaccines and therein may be useful biomarkers for vaccine candidate efficacy/durability in preclinical/clinical studies.We further speculate that investigating the manner in which antigen-specific MBCs are distributed across subclusters may provide insight into the optimal design of influenza virus/coronaviral vaccines that could subvert antigenic imprinting.Recent high-throughput proteomic screening and other techniques have helped refine our understanding of circulating MBC subphenotypes; CD45RB expression identifies a naïve-proximal, apparent 'early' population of CD27- MBCs.CD95 expression identifies a subset of naïve-distal, 'advanced' CD45RB+CD27+CD73+ MBCs and may contribute to plasmablast differentiation in response to soluble CD95L.Nonclassical MBC-like cells (CD19hiCD11c+CD21loCD27+/–CXCR3+/–T-bet+) are T cell-dependent, of germinal center-independent origin, seed secondary germinal centers, and develop into antibody-secreting cells during recall responses. The overarching logos of mammalian memory B cells (MBCs) is to cache the potential for enhanced antibody production upon secondary exposure to cognate antigenic determinants. However, substantial phenotypic diversity has been identified across MBCs, hinting at the existence of unique origins or subfunctions within this compartment. Herein, we discuss recent advancements in human circulatory MBC subphenotyping as driven by high-throughput cell surface marker analysis and other approaches, as well as speculated and substantiated subfunctions. With this in mind, we hypothesize that the relative induction of specific circulatory MBC subsets might be used as a biomarker for optimally durable vaccines and inform vaccination strategies to subvert antigenic imprinting in the context of highly mutable pathogens such as influenza virus or SARS-CoV-2. The overarching logos of mammalian memory B cells (MBCs) is to cache the potential for enhanced antibody production upon secondary exposure to cognate antigenic determinants. However, substantial phenotypic diversity has been identified across MBCs, hinting at the existence of unique origins or subfunctions within this compartment. Herein, we discuss recent advancements in human circulatory MBC subphenotyping as driven by high-throughput cell surface marker analysis and other approaches, as well as speculated and substantiated subfunctions. With this in mind, we hypothesize that the relative induction of specific circulatory MBC subsets might be used as a biomarker for optimally durable vaccines and inform vaccination strategies to subvert antigenic imprinting in the context of highly mutable pathogens such as influenza virus or SARS-CoV-2. Through the secretion of antibodies that can limit pathogen acquisition and infectious disease, B cells and their progeny are often integral contributors to vaccination strategies and host defense against microbial agents, such as influenza A virus (IAV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1.Guthmiller J.J. et al.B cell responses against influenza viruses: short-lived humoral immunity against a life-long threat.Viruses. 2021; 13: 965Crossref PubMed Scopus (8) Google Scholar,2.Sadarangani M. et al.Immunological mechanisms of vaccine-induced protection against COVID-19 in humans.Nat. Rev. Immunol. 2021; 21: 475-484Crossref PubMed Scopus (141) Google Scholar]. Broadly, the landscape of B cell immunity can be described as a function of two components: the primary production of antibodies that can directly mediate protection, and the cached potential to produce more antibodies in a rapid and augmented fashion upon secondary exposure, stored in the form of memory B cells (MBCs) (see Glossary). Under ideal conditions, a single exposure to pathogen-derived antigenic determinants, whether through infection or vaccination, can elicit life-long protection via the net contribution of these and other (e.g., T cell-related) factors. However, this frequently is not the case, with protection diminishing over time to some degree, in a context-specific manner [3.Gu X.X. et al.Waning immunity and microbial vaccines-workshop of the national institute of allergy and infectious diseases.Clin. Vaccine Immunol. 2017; 24e00034-17Crossref Scopus (31) Google Scholar]. Although the immunological determinants of sustained versus depreciating immunity have not been fully resolved, it can be reasonably assumed that the optimized induction of MBC immunity should represent a high-priority objective in the development of novel vaccine candidates against antibody-susceptible pathogens. At the same time however, MBCs may also sometimes act as a detriment to sustained immunity, specifically in the context of highly mutable pathogens, such as IAV. For instance, it is reasonably well established that early-life exposure to dominant circulating IAV strains can elicit an antigenic 'imprint' within individuals, wherein memory responses to these strains are continually back-boosted by subsequent exposure to antigenically drifted epidemic strains [4.Henry C. et al.From original antigenic sin to the universal influenza virus vaccine.Trends Immunol. 2018; 39: 70-79Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar]. While this may be innocuous or beneficial in some instances [5.Gostic K.M. et al.Potent protection against H5N1 and H7N9 influenza via childhood hemagglutinin imprinting.Science. 2016; 354: 722-726Crossref PubMed Scopus (238) Google Scholar], this 'antigenic seniority' is also thought to sometimes occur at the expense of efficacious antibody induction following exposure to heterosubtypic strains [6.Arevalo C.P. et al.Original antigenic sin priming of influenza virus hemagglutinin stalk antibodies.Proc. Natl. Acad. Sci. U. S. A. 2020; 117: 1-7Crossref Scopus (24) Google Scholar] and may narrowly focus antibodies generated in homosubtypic contexts against drift-prone epitopes [7.Huang K.Y.A. et al.Focused antibody response to influenza linked to antigenic drift.J. Clin. Invest. 2015; 125: 2631-2645Crossref PubMed Scopus (81) Google Scholar]. This concept, in its detrimental form, is known as original antigenic sin (OAS) [8.Francis T. On the doctrine of original antigenic sin.Proc. Am. Philos. Soc. 1960; 104: 572-578Google Scholar]. Further complicating this interplay is the phenomenon of epitope immunodominance [9.Angeletti D. Yewdell J.W. Understanding and manipulating viral immunity: antibody immunodominance enters center stage.Trends Immunol. 2018; 39: 549-561Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar,10.Knight M. et al.Imprinting, immunodominance, and other impediments to generating broad influenza immunity.Immunol. Rev. 2020; 296: 191-204Crossref PubMed Scopus (13) Google Scholar]. For example, within hemagglutinin (HA), IAV's receptor-binding glycoprotein and primary antigenic determinant, epitopes in the membrane-distal 'head' domain are far more efficient at inducing immune activation compared with the more proximal 'stalk' domain [9.Angeletti D. Yewdell J.W. Understanding and manipulating viral immunity: antibody immunodominance enters center stage.Trends Immunol. 2018; 39: 549-561Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar]. This is a particular issue given that evolutionary pressures from natural selection and human interventions (e.g., vaccines) drive continuous permissive mutation and rapid evolution of the head domain [11.Kirkpatrick E. et al.The influenza virus hemagglutinin head evolves faster than the stalk domain.Sci. Rep. 2018; 8: 1-14Crossref PubMed Scopus (96) Google Scholar], enabling evasion of pre-existing neutralizing antibody immunity. In comparison, the stalk domain is more evolutionarily conserved and less permissive to mutation [11.Kirkpatrick E. et al.The influenza virus hemagglutinin head evolves faster than the stalk domain.Sci. Rep. 2018; 8: 1-14Crossref PubMed Scopus (96) Google Scholar,12.Heaton N.S. et al.Genome-wide mutagenesis of influenza virus reveals unique plasticity of the hemagglutinin and NS1 proteins.Proc. Natl. Acad. Sci. U. S. A. 2013; 110: 20248-20253Crossref PubMed Scopus (129) Google Scholar]; consequently, antibody responses against this region often neutralize a broader diversity of IAV strains. However, it is often noted that such stalk-specific responses are poorly activated relative to head-specific responses by immunization [13.Angeletti D. et al.Outflanking immunodominance to target subdominant broadly neutralizing epitopes.Proc. Natl. Acad. Sci. U. S. A. 2019; 116: 13474-13479Crossref PubMed Scopus (42) Google Scholar,14.Angeletti D. et al.Defining B cell immunodominance to viruses.Nat. Immunol. 2017; 18: 456-463Crossref PubMed Scopus (134) Google Scholar], in some cases as a result of pre-existing head-specific memory [15.Andrews S.F. et al.Immune history profoundly affects broadly protective B cell responses to influenza.Sci. Transl. Med. 2015; 7: 316ra192Crossref PubMed Scopus (242) Google Scholar]. Therefore, understanding and overcoming this MBC-mediated barrier is important for the development of broadly protective universal influenza vaccines. Which variables dictate the integrity of MBC-mediated immunity? One notable factor is the engagement of T cell help, by means of T follicular helper (TFH) and B2 cell activation within lymphoid tissues in mice and humans [16.Kurosaki T. et al.Memory B cells.Nat. Rev. Immunol. 2015; 15: 149-159Crossref PubMed Scopus (385) Google Scholar]. This process results in the cycling of activated B cells through germinal centers (GCs) to promote affinity maturation of their B cell receptors (BCRs) for cognate antigen, while also facilitating enhanced MBC production relative to T cell-independent activation pathways [17.Victora G.D. Nussenzweig M.C. Germinal centers.Annu. Rev. Immunol. 2022; 40: 413-442Crossref Scopus (5) Google Scholar]. Notably, while MBCs are often referred to (and assessed) as an aggregate population, it is known that, even outside of BCR-intrinsic differences such as isotype, germline affinity, and affinity maturation, these cells are not homogenous, with a number of subsets having been identified in various contexts (Box 1). Although some work has been conducted to investigate the relative contribution of MBC subpopulations to different functions [18.Zuccarino-Catania G.V. et al.CD80 and PD-L2 define functionally distinct memory B cell subsets that are independent of antibody isotype.Nat. Immunol. 2014; 15: 631-637Crossref PubMed Scopus (236) Google Scholar], the full scope of this system remains to be fully elucidated and is a burgeoning area of active research. Given this diversity, we hypothesize that if specific circulating MBC subsets or distributions can be observed to correlate with vaccine efficacy, or be unambiguously implicated in participating in protective outcomes against infection through experimentation, these subsets might serve as biomarkers for efficacy and/or durability of candidate vaccine-mediated immune memory (Figure 1, Key figure). In addition, we posit that a better understanding of MBC subphenotypes may enhance our understanding of antigenic imprinting, informing the development of OAS-subversive vaccination strategies. In support of these positions, we discuss: (i) subfunctions that might be performed across a heterogenous MBC population, (ii) recent subphenotyping efforts highlighting CD19hiCD11c+ nonclassical and CD45RB+CD27+CD73+CD95+ circulating MBCs as potential subsets of interest for biomarker development, and (iii) the potential utility of human seasonal coronavirus (hCoV) spike-specific MBC subphenotyping in optimizing coronaviral vaccines.Box 1(Why) Is MBC diversity necessary?The overarching purpose of B cell memory is to enhance the quality and quantity of secondary antibody responses against a given antigen, thereby optimizing protection against subsequent homologous infections. However, phenotypic heterogeneity of cell surface markers within the MBC compartment raises questions about further specialization of function and purpose. On one hand, circulating MBC subphenotypes may arise as collateral byproducts of their specific activational environment (e.g., germinal center, extrafollicular cortex [19.Jenks S.A. et al.Distinct effector B cells induced by unregulated Toll-like receptor 7 contribute to pathogenic responses in systemic lupus erythematosus.Immunity. 2018; 49: 725-739Abstract Full Text Full Text PDF PubMed Scopus (315) Google Scholar,20.Song W. et al.Development of Tbet- and CD11c-expressing B cells in a viral infection requires T follicular helper cells outside of germinal centers.Immunity. 2022; 55: 1-18Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar]) or timeframe (e.g., new versus mature/persistent GCs [21.Turner J.S. et al.SARS-CoV-2 mRNA vaccines induce persistent human germinal centre responses.Nature. 2021; 596: 109-113Crossref PubMed Scopus (204) Google Scholar,22.Yewdell W.T. et al.Temporal dynamics of persistent germinal centers and memory B cell differentiation following respiratory virus infection.Cell Rep. 2021; 37109961Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar,77.Weisel F.J. et al.A temporal switch in the germinal center determines differential output of memory B and plasma cells.Immunity. 2016; 44: 116-130Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar]); in such a case, these subsets might possess relatively homogenous functional capabilities outside of those dependent on BCR-intrinsic factors (respective isotype, affinity, mutational load). On the other hand, it is reasonably speculated that MBC subphenotypes may exhibit somewhat distinct operational programming and fulfill different functional or purpose-based roles. Ultimately, we argue that both scenarios likely occur at some balance.Outside of 'typical' functions, what operational attributes might a diverse circulatory MBC population theoretically need to possess? One might be that of a tissue-resident fate; in addition to MBCs that circulate throughout the blood and secondary lymphoid organs, in the case of mucosal infection it would be pertinent to provide additional protection at sites of exposure [23.Tan H.-X. et al.Lung-resident memory B cells established after pulmonary influenza infection display distinct transcriptional and phenotypic profiles.Sci. Immunol. 2022; 7: eabf5314Crossref PubMed Scopus (4) Google Scholar, 24.Allie S.R. et al.The establishment of resident memory B cells in the lung requires local antigen encounter.Nat. Immunol. 2019; 20: 97-108Crossref PubMed Scopus (130) Google Scholar, 25.Allie S.R. Randall T.D. Resident memory B cells.Viral Immunol. 2020; 33: 282-293Crossref PubMed Scopus (16) Google Scholar, 26.Barker K.A. et al.Lung-resident memory B cells protect against bacterial pneumonia.J. Clin. Invest. 2021; 131e141810Crossref PubMed Scopus (20) Google Scholar]. Requirements for tissue homing and specific function likely further differ between specific tissues (such as the brain, gut, lung) given the disparate microbial and immunological conditions at different sites. Similarly, it might be advantageous to store MBCs long-term in the bone marrow [27.Glass D.R. et al.An integrated multi-omic single-cell atlas of human B cell identity.Immunity. 2020; 53: 217-232Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, 28.Weisel N.M. et al.Surface phenotypes of naive and memory B cells in mouse and human tissues.Nat. Immunol. 2022; 23: 135-145Crossref PubMed Scopus (3) Google Scholar, 29.Riedel R. et al.Discrete populations of isotype-switched memory B lymphocytes are maintained in murine spleen and bone marrow.Nat. Commun. 2020; 11: 1-14Crossref PubMed Scopus (17) Google Scholar], along with other durable immune subsets such as long-lived plasma cells (LLPCs) [30.Turner J.S. et al.SARS-CoV-2 infection induces long-lived bone marrow plasma cells in humans.Nature. 2021; 595: 421-425Crossref PubMed Scopus (193) Google Scholar]; these might constitute chronic reservoirs of protection against systemic inflammatory agents. Collaterally, MBCs might require regulatory capabilities in some contexts, such as suppressing IFNγ-producing T cell responses and preventing chronic graft-versus host disease [31.Iwata Y. et al.Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells.Blood. 2011; 117: 530-541Crossref PubMed Scopus (822) Google Scholar,32.Khoder A. et al.Regulatory B cells are enriched within the IgM memory and transitional subsets in healthy donors but are deficient in chronic GVHD.Blood. 2014; 124: 2034-2045Crossref PubMed Scopus (142) Google Scholar], or express microbe-specific functional programs such as those relating to combatting bacterial pathogens versus constraining bacterial commensals. Do transient MBC phenotypes exist which undergo further selection against pathogen-derived antigens and autoantigens in circulation and in other peripheral sites? Do specific transcriptional programs limit GC re-entry of newly formed MBCs during a primary response to promote continuous clonal engagement and diversification? Conversely, are specific subsets phenotypically prioritized for re-entry into secondary GCs [18.Zuccarino-Catania G.V. et al.CD80 and PD-L2 define functionally distinct memory B cell subsets that are independent of antibody isotype.Nat. Immunol. 2014; 15: 631-637Crossref PubMed Scopus (236) Google Scholar,33.Mesin L. et al.Restricted clonality and limited germinal center reentry characterize memory B cell reactivation by boosting.Cell. 2020; 180: 92-106Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar]? Do MBC phenotypes correlate with the immunodominant status of epitopes or antigens [34.Johnson J.L. et al.The transcription factor T-bet resolves memory B cell subsets with distinct tissue distributions and antibody specificities in mice and humans.Immunity. 2020; 52: 842-855Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar] in potential evolutionary expectation of distinct reactivation or functional requirements for highly versus lowly visible immune determinants? Are certain subsets of MBCs more secluded or refractory to reactivation than others to reduce metabolic shift and energy consumption in mild re-infection contexts, while being capable of responding to substantial re-infections? These are but a few possibilities; notably, whether operational imprints overlap to produce combinatorial MBC subsets also remains unanswered. Although some of these functions have been established, further research is required to substantiate the relationship between phenotype and function in the circulatory MBC compartment. The overarching purpose of B cell memory is to enhance the quality and quantity of secondary antibody responses against a given antigen, thereby optimizing protection against subsequent homologous infections. However, phenotypic heterogeneity of cell surface markers within the MBC compartment raises questions about further specialization of function and purpose. On one hand, circulating MBC subphenotypes may arise as collateral byproducts of their specific activational environment (e.g., germinal center, extrafollicular cortex [19.Jenks S.A. et al.Distinct effector B cells induced by unregulated Toll-like receptor 7 contribute to pathogenic responses in systemic lupus erythematosus.Immunity. 2018; 49: 725-739Abstract Full Text Full Text PDF PubMed Scopus (315) Google Scholar,20.Song W. et al.Development of Tbet- and CD11c-expressing B cells in a viral infection requires T follicular helper cells outside of germinal centers.Immunity. 2022; 55: 1-18Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar]) or timeframe (e.g., new versus mature/persistent GCs [21.Turner J.S. et al.SARS-CoV-2 mRNA vaccines induce persistent human germinal centre responses.Nature. 2021; 596: 109-113Crossref PubMed Scopus (204) Google Scholar,22.Yewdell W.T. et al.Temporal dynamics of persistent germinal centers and memory B cell differentiation following respiratory virus infection.Cell Rep. 2021; 37109961Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar,77.Weisel F.J. et al.A temporal switch in the germinal center determines differential output of memory B and plasma cells.Immunity. 2016; 44: 116-130Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar]); in such a case, these subsets might possess relatively homogenous functional capabilities outside of those dependent on BCR-intrinsic factors (respective isotype, affinity, mutational load). On the other hand, it is reasonably speculated that MBC subphenotypes may exhibit somewhat distinct operational programming and fulfill different functional or purpose-based roles. Ultimately, we argue that both scenarios likely occur at some balance. Outside of 'typical' functions, what operational attributes might a diverse circulatory MBC population theoretically need to possess? One might be that of a tissue-resident fate; in addition to MBCs that circulate throughout the blood and secondary lymphoid organs, in the case of mucosal infection it would be pertinent to provide additional protection at sites of exposure [23.Tan H.-X. et al.Lung-resident memory B cells established after pulmonary influenza infection display distinct transcriptional and phenotypic profiles.Sci. Immunol. 2022; 7: eabf5314Crossref PubMed Scopus (4) Google Scholar, 24.Allie S.R. et al.The establishment of resident memory B cells in the lung requires local antigen encounter.Nat. Immunol. 2019; 20: 97-108Crossref PubMed Scopus (130) Google Scholar, 25.Allie S.R. Randall T.D. Resident memory B cells.Viral Immunol. 2020; 33: 282-293Crossref PubMed Scopus (16) Google Scholar, 26.Barker K.A. et al.Lung-resident memory B cells protect against bacterial pneumonia.J. Clin. Invest. 2021; 131e141810Crossref PubMed Scopus (20) Google Scholar]. Requirements for tissue homing and specific function likely further differ between specific tissues (such as the brain, gut, lung) given the disparate microbial and immunological conditions at different sites. Similarly, it might be advantageous to store MBCs long-term in the bone marrow [27.Glass D.R. et al.An integrated multi-omic single-cell atlas of human B cell identity.Immunity. 2020; 53: 217-232Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, 28.Weisel N.M. et al.Surface phenotypes of naive and memory B cells in mouse and human tissues.Nat. Immunol. 2022; 23: 135-145Crossref PubMed Scopus (3) Google Scholar, 29.Riedel R. et al.Discrete populations of isotype-switched memory B lymphocytes are maintained in murine spleen and bone marrow.Nat. Commun. 2020; 11: 1-14Crossref PubMed Scopus (17) Google Scholar], along with other durable immune subsets such as long-lived plasma cells (LLPCs) [30.Turner J.S. et al.SARS-CoV-2 infection induces long-lived bone marrow plasma cells in humans.Nature. 2021; 595: 421-425Crossref PubMed Scopus (193) Google Scholar]; these might constitute chronic reservoirs of protection against systemic inflammatory agents. Collaterally, MBCs might require regulatory capabilities in some contexts, such as suppressing IFNγ-producing T cell responses and preventing chronic graft-versus host disease [31.Iwata Y. et al.Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells.Blood. 2011; 117: 530-541Crossref PubMed Scopus (822) Google Scholar,32.Khoder A. et al.Regulatory B cells are enriched within the IgM memory and transitional subsets in healthy donors but are deficient in chronic GVHD.Blood. 2014; 124: 2034-2045Crossref PubMed Scopus (142) Google Scholar], or express microbe-specific functional programs such as those relating to combatting bacterial pathogens versus constraining bacterial commensals. Do transient MBC phenotypes exist which undergo further selection against pathogen-derived antigens and autoantigens in circulation and in other peripheral sites? Do specific transcriptional programs limit GC re-entry of newly formed MBCs during a primary response to promote continuous clonal engagement and diversification? Conversely, are specific subsets phenotypically prioritized for re-entry into secondary GCs [18.Zuccarino-Catania G.V. et al.CD80 and PD-L2 define functionally distinct memory B cell subsets that are independent of antibody isotype.Nat. Immunol. 2014; 15: 631-637Crossref PubMed Scopus (236) Google Scholar,33.Mesin L. et al.Restricted clonality and limited germinal center reentry characterize memory B cell reactivation by boosting.Cell. 2020; 180: 92-106Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar]? Do MBC phenotypes correlate with the immunodominant status of epitopes or antigens [34.Johnson J.L. et al.The transcription factor T-bet resolves memory B cell subsets with distinct tissue distributions and antibody specificities in mice and humans.Immunity. 2020; 52: 842-855Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar] in potential evolutionary expectation of distinct reactivation or functional requirements for highly versus lowly visible immune determinants? Are certain subsets of MBCs more secluded or refractory to reactivation than others to reduce metabolic shift and energy consumption in mild re-infection contexts, while being capable of responding to substantial re-infections? These are but a few possibilities; notably, whether operational imprints overlap to produce combinatorial MBC subsets also remains unanswered. Although some of these functions have been established, further research is required to substantiate the relationship between phenotype and function in the circulatory MBC compartment. Recent work using unbiased high-throughput screening technologies to assess B lymphocyte populations has greatly improved our understanding of MBC diversity (Figure 2). For instance, mass cytometry has been valuable in deeply interrogating cell surface marker-based subphenotypes within human peripheral blood B cell populations during homeostasis [27.Glass D.R. et al.An integrated multi-omic single-cell atlas of human B cell identity.Immunity. 2020; 53: 217-232Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar]. Using this highly multiplexed approach, six distinct circulating MBC phenotypes were found that were definable based on the combinatorial expression of CD27, CD73, CD95, CD19, CD11c, and the CD45 isoform CD45RB. With the exception of CD11c (a typically innate cell-restricted integrin), this set of markers (along with a comprehensive list of over 63 others) was independently validated as positively identifying human splenic MBCs from naïve B cells in other recent flow cytometry-based surface screening efforts [28.Weisel N.M. et al.Surface phenotypes of naive and memory B cells in mouse and human tissues.Nat. Immunol. 2022; 23: 135-145Crossref PubMed Scopus (3) Google Scholar]. Notably, among these circulating subtypes was a CD45RB+CD27–CD73– cluster: among MBCs, these cells were the most proximal to naïve B cells and presented as the root to an apparent continuum of MBC subsets characterized by the iterative acquisition of CD27, CD73, and CD95 expression [27.Glass D.R. et al.An integrated multi-omic single-cell atlas of human B cell identity.Immunity. 2020; 53: 217-232Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar]. The localization of this cluster, along with its largely unswitched repertoire (referring to isotype switching), low metabolic/transcriptional activity, moderate mutational burden, and relative unresponsiveness to BCR engagement/CD40L stimulation suggested that it represented an early MBC subpopulation. Although circulating CD45RB+CD27– MBCs have been described in the past [35.Koethe S. et al.CD45RB glycosylation is specifically regulated during human peripheral B cell differentiation.J. Leukoc. Biol. 2011; 90: 5-19Crossref PubMed Scopus (22) Google Scholar], the relative position of this population as an early memory phenotype is newly described here [27.Glass D.R. et al.An integrated multi-omic single-cell atlas of human B cell identity.Immunity. 2020; 53: 217-232Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar]. Potentially in line with this population, other work has newly defined CD11a and CD200 as potential positive and negative identifiers of isotype-switched CD27– MBCs, respectively [28.Weisel N.M. et al.Surface phenotypes of naive and memory B cells in mouse and human tissues.Nat. Immunol. 2022; 23: 135-145Crossref PubMed Scopus (3) Google Scholar]. If this is indeed an 'early' MBC population [27.Glass D.R. et al.An integrated multi-omic single-cell atlas of human B cell identity.Immunity. 2020; 53: 217-232Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar], a relative bottleneck of antigen-specific MBCs in this compartment may be a useful potential indicator of inefficient immune activation by vaccine candidates, given that one would likely expect a more diversified or 'advanced' MBC response to an optimal vaccine. At the other end of the spectrum, two naïve-distal MBC clusters were noted in this study; the first expressed high amounts of CD95 along with CD45RB, CD27, and CD73, while the second was enriched for CD19 and CD11c while displaying relatively low amounts of CD45RB, CD27, CD73, and CD95 [27.Glass D.R. et al.An integrated multi-omic single-cell atlas of human B cell identity.Immunity. 2020; 53: 217-232Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar]. These clusters were of interest given that they clearly segregated from one another, and quite far from naïve cells, within the uniform manifold approximatio
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