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• W2938678047 abstract "B cells and the antibodies they produce have a deeply penetrating influence on human physiology. Here, we review current understanding of how B cell responses are initiated; the different paths to generate short- and long-lived plasma cells, germinal center cells, and memory cells; and how each path impacts antibody diversity, selectivity, and affinity. We discuss how basic research is informing efforts to generate vaccines that induce broadly neutralizing antibodies against viral pathogens, revealing the special features associated with allergen-reactive IgE responses and uncovering the antibody-independent mechanisms by which B cells contribute to health and disease. B cells and the antibodies they produce have a deeply penetrating influence on human physiology. Here, we review current understanding of how B cell responses are initiated; the different paths to generate short- and long-lived plasma cells, germinal center cells, and memory cells; and how each path impacts antibody diversity, selectivity, and affinity. We discuss how basic research is informing efforts to generate vaccines that induce broadly neutralizing antibodies against viral pathogens, revealing the special features associated with allergen-reactive IgE responses and uncovering the antibody-independent mechanisms by which B cells contribute to health and disease. The importance of B cells to human health is hard to overstate. Vaccines capable of eradicating disease activate B cells, cancer checkpoint blockade therapies are produced using B cells, and B cell deficiencies have devastating impacts (Figure 1). B cells have been a subject of fascination since at least the 1800s, when early microscopists observed foci of mitotic figures in lymphoid tissues that they named germinal centers (Flemming, 1885Flemming W. Studien uber Regeneration der Gewebe.Arch f Mikr Anat. 1885; 24: 50-91Crossref Scopus (33) Google Scholar). The notion of a humoral branch to immunity emerged from the work of Ehrlich, 1908Ehrlich, P. (1908). Partial cell functions. Nobel Lecture, December 11, 1908, https://www.nobelprize.org/prizes/medicine/1908/ehrlich/lecture/.Google Scholar and contemporaries studying B cells in the early 1900s. Efforts to understand how we could make antibodies from B cells against almost any foreign surface while usually avoiding making them against self, led to Burnet’s clonal selection theory (Burnet, 1960Burnet, F.M. (1960). Immunological recognition of self. Nobel Lecture, December 12, 1960, https://www.nobelprize.org/prizes/medicine/1960/Burnet/lecture/.Google Scholar). This was followed by the molecular definition of how a diversity of immunoglobulins can arise by gene rearrangement in developing B cells (Tonegawa, 1987Tonegawa, S. (1987). Somatic Generation of Immune Diversity. Nobel Lecture, December 8, 1987, https://www.nobelprize.org/prizes/medicine/1987/tonegawa/lecture/.Google Scholar). Recombination activating gene (RAG)-dependent processes of V-(D)-J rearrangement of immunoglobulin (Ig) gene segments in developing B cells are now known to be able to generate an enormous amount of antibody diversity (theoretically at least 1016 possible variants) (Briney et al., 2019Briney B. Inderbitzin A. Joyce C. Burton D.R. Commonality despite exceptional diversity in the baseline human antibody repertoire.Nature. 2019; 566: 393-397Crossref PubMed Scopus (18) Google Scholar, Schatz et al., 1989Schatz D.G. Oettinger M.A. Baltimore D. The V(D)J recombination activating gene, RAG-1.Cell. 1989; 59: 1035-1048Abstract Full Text PDF PubMed Scopus (895) Google Scholar). With so much already known, B cell biology might be considered “done” with only incremental advances still to be made, but instead, there is great activity in the field today with numerous major challenges that remain. For example, efforts are underway to develop vaccines that induce broadly neutralizing antibody responses, to understand how autoantigen- and allergen-reactive antibodies arise, and to harness B cell-depletion therapies to correct non-autoantibody-mediated diseases, making it evident that there is still an enormous amount we do not know about B cells and much work to be done. In this review, we give an overview of how B cells travel throughout the body surveying for antigen, how they respond upon antigen encounter, how they go on to become IgM-, IgG-, IgA-, or IgE-secreting plasma cells (PCs) or memory B (Bmem) cells, and how they contribute to a variety of disease states including autoimmunity, allergy, and cancer. We highlight newer findings in each area while guiding the reader to recent reviews for deeper assessment of each topic. The initiation of humoral immune responses requires that rare antigen-reactive B cells come in contact with antigen (Figure 2). These encounters predominantly occur in secondary (or peripheral) lymphoid tissues—including the spleen, lymph nodes (LNs), and Peyer’s patches (PPs)—and are promoted by two core processes. First, the lymphoid tissues are specialized to filter body fluids—blood, lymph, and mucosal contents—and to capture and display foreign antigens for B cells to “see.” Second, these tissues support the continual recruitment of lymphocytes from the blood across specialized lymphocyte-binding endothelial cells and their movement into compartments (lymphoid follicles) where incoming antigens are focused (Cyster, 2010Cyster J.G. B cell follicles and antigen encounters of the third kind.Nat. Immunol. 2010; 11: 989-996Crossref PubMed Scopus (170) Google Scholar, Schulz et al., 2016Schulz O. Hammerschmidt S.I. Moschovakis G.L. Förster R. Chemokines and Chemokine Receptors in Lymphoid Tissue Dynamics.Annu. Rev. Immunol. 2016; 34: 203-242Crossref PubMed Google Scholar). The initial cell types that handle incoming antigens differs between the lymphoid tissue types, but the overall principle of making intact antigen available for B cell encounter is similar. In LNs, for example, specialized macrophages exist in a subcapsular location that capture particulate antigens from the lymph and transport them in a directional manner along their length to tail processes that contact follicular B cells (Cyster, 2010Cyster J.G. B cell follicles and antigen encounters of the third kind.Nat. Immunol. 2010; 11: 989-996Crossref PubMed Scopus (170) Google Scholar). Embedded within the center of lymphoid follicles are follicular dendritic cells (FDCs), specialized stromal cells that are highly efficient at capturing and displaying opsonized (antibody- and/or complement-coated) antigens on their extensive network of dendritic processes (Allen and Cyster, 2008Allen C.D. Cyster J.G. Follicular dendritic cell networks of primary follicles and germinal centers: phenotype and function.Semin. Immunol. 2008; 20: 14-25Crossref PubMed Scopus (233) Google Scholar, Heesters et al., 2014Heesters B.A. Myers R.C. Carroll M.C. Follicular dendritic cells: dynamic antigen libraries.Nat. Rev. Immunol. 2014; 14: 495-504Crossref PubMed Scopus (126) Google Scholar). The gene expression profile of FDCs has long been elusive due to their rarity and difficulty to isolate but has recently been obtained using single-cell RNA sequencing (RNA-seq) technology (Rodda et al., 2018Rodda L.B. Lu E. Bennett M.L. Sokol C.L. Wang X. Luther S.A. Barres B.A. Luster A.D. Ye C.J. Cyster J.G. Single-Cell RNA Sequencing of Lymph Node Stromal Cells Reveals Niche-Associated Heterogeneity.Immunity. 2018; 48: 1014-1028Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar). In contrast to most antigen-capturing cells, FDCs are non-phagocytic and can retain and display intact antigens on their cell surface for periods of weeks, although this may involve endocytic recycling (Heesters et al., 2014Heesters B.A. Myers R.C. Carroll M.C. Follicular dendritic cells: dynamic antigen libraries.Nat. Rev. Immunol. 2014; 14: 495-504Crossref PubMed Scopus (126) Google Scholar). B cell migration to follicles is guided by the chemokine CXCL13, the ligand for CXCR5, which is made by FDCs and by other follicle-associated stromal cells. Within the follicle, B cells migrate continuously along the follicular stroma in a non-directional fashion, at ∼6 μm per minute, surveying subcapsular macrophages and FDCs for surface-displayed antigen or for soluble antigens in their environment (Batista and Harwood, 2009Batista F.D. Harwood N.E. The who, how and where of antigen presentation to B cells.Nat. Rev. Immunol. 2009; 9: 15-27Crossref PubMed Scopus (377) Google Scholar, Cyster, 2010Cyster J.G. B cell follicles and antigen encounters of the third kind.Nat. Immunol. 2010; 11: 989-996Crossref PubMed Scopus (170) Google Scholar, Qi et al., 2014Qi H. Kastenmüller W. Germain R.N. Spatiotemporal basis of innate and adaptive immunity in secondary lymphoid tissue.Annu. Rev. Cell Dev. Biol. 2014; 30: 141-167Crossref PubMed Scopus (62) Google Scholar). Lymphoid stromal cells within follicles as well as in other parts of lymphoid tissues are a source of BAFF (TNFRSF13b), a critical B cell survival factor (Cremasco et al., 2014Cremasco V. Woodruff M.C. Onder L. Cupovic J. Nieves-Bonilla J.M. Schildberg F.A. Chang J. Cremasco F. Harvey C.J. Wucherpfennig K. et al.B cell homeostasis and follicle confines are governed by fibroblastic reticular cells.Nat. Immunol. 2014; 15: 973-981Crossref PubMed Scopus (119) Google Scholar, Rodda et al., 2018Rodda L.B. Lu E. Bennett M.L. Sokol C.L. Wang X. Luther S.A. Barres B.A. Luster A.D. Ye C.J. Cyster J.G. Single-Cell RNA Sequencing of Lymph Node Stromal Cells Reveals Niche-Associated Heterogeneity.Immunity. 2018; 48: 1014-1028Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar). B cell access to the outer parts of the follicle is promoted by a second guidance factor, the oxysterol 7α,25-HC, that is produced by stromal cells in these regions and acts via the chemoattractant receptor EBI2 (GPR183) (Cyster et al., 2014Cyster J.G. Dang E.V. Reboldi A. Yi T. 25-Hydroxycholesterols in innate and adaptive immunity.Nat. Rev. Immunol. 2014; 14: 731-743Crossref PubMed Scopus (117) Google Scholar, Gatto and Brink, 2013Gatto D. Brink R. B cell localization: regulation by EBI2 and its oxysterol ligand.Trends Immunol. 2013; 14 (446–443)Google Scholar). If, after several hours of surveillance, antigen is not encountered, B cells exit lymphoid tissues in response to sphingosine-1-phosphate (S1P) sensing via their S1PR1 receptor (Cyster and Schwab, 2012Cyster J.G. Schwab S.R. Sphingosine-1-phosphate and lymphocyte egress from lymphoid organs.Annu. Rev. Immunol. 2012; 30: 69-94Crossref PubMed Scopus (446) Google Scholar). From the spleen, B cells exit into blood vessels and, from LNs and PPs, into lymphatic vessels. Once in the circulatory fluid, B cells can travel to another lymphoid tissue in a matter of minutes to continue their surveillance program. The exact mechanisms controlling the times that B cells spend in a lymphoid tissue have not been fully delineated, although a modeling study suggested that dwell time might be accounted for by the migration properties of the B cells and their propensity to exit versus remain in the tissue upon each lymphatic sinus encounter (Grigorova et al., 2010Grigorova I.L. Panteleev M. Cyster J.G. Lymph node cortical sinus organization and relationship to lymphocyte egress dynamics and antigen exposure.Proc. Natl. Acad. Sci. USA. 2010; 107: 20447-20452Crossref PubMed Scopus (0) Google Scholar). Recent work has shown that lymphocyte entry into and exit from lymphoid tissues has a circadian component; more lymphocytes accumulate in lymphoid tissues during the period of higher physical activity (Druzd et al., 2017Druzd D. Matveeva O. Ince L. Harrison U. He W. Schmal C. Herzel H. Tsang A.H. Kawakami N. Leliavski A. et al.Lymphocyte Circadian Clocks Control Lymph Node Trafficking and Adaptive Immune Responses.Immunity. 2017; 46: 120-132Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar). Neuronal activity may contribute to this circadian behavior because lymphocyte adrenergic receptor signaling can promote CXCR4-mediated retention in LNs (Suzuki et al., 2016Suzuki K. Hayano Y. Nakai A. Furuta F. Noda M. Adrenergic control of the adaptive immune response by diurnal lymphocyte recirculation through lymph nodes.J. Exp. Med. 2016; 213: 2567-2574Crossref PubMed Scopus (42) Google Scholar). Upon encounter with antigen, signaling via the B cell receptor (BCR) initiates B cell activation (Figure 2). The actual mechanism by which antigen binding activates the BCR remains an area of active investigation. One model proposes that antigen binding leads to clustering of BCRs on the membrane to initiate signaling (Liu et al., 2016Liu W. Wang H. Xu C. Antigen Receptor Nanoclusters: Small Units with Big Functions.Trends Immunol. 2016; 37: 680-689Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar). Conversely, an alternative model is that BCR clusters preexist before antigen encounter, and antigen binding dissociates these clusters enabling signaling to occur (Yang and Reth, 2016Yang J. Reth M. Receptor Dissociation and B-Cell Activation.Curr. Top. Microbiol. Immunol. 2016; 393: 27-43PubMed Google Scholar). A further variant on these models is that the mobility of the BCR, relative to coreceptor molecules, may be altered by antigen binding (Liu et al., 2016Liu W. Wang H. Xu C. Antigen Receptor Nanoclusters: Small Units with Big Functions.Trends Immunol. 2016; 37: 680-689Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, Yang and Reth, 2016Yang J. Reth M. Receptor Dissociation and B-Cell Activation.Curr. Top. Microbiol. Immunol. 2016; 393: 27-43PubMed Google Scholar). Naive B cells express membrane-bound immunoglobulin of the IgM and/or IgD isotypes, which lack significant intracellular domains, thus signal transduction relies on associated molecules. In particular, Igα and Igβ are pre-associated with IgM and IgD and contain intracellular ITAM motifs that can be phosphorylated by tyrosine kinases (Kurosaki et al., 2010Kurosaki T. Shinohara H. Baba Y. B cell signaling and fate decision.Annu. Rev. Immunol. 2010; 28: 21-55Crossref PubMed Scopus (189) Google Scholar, Yang and Reth, 2016Yang J. Reth M. Receptor Dissociation and B-Cell Activation.Curr. Top. Microbiol. Immunol. 2016; 393: 27-43PubMed Google Scholar). The Syk tyrosine kinase is essential for BCR signaling while Src-family kinases (SFK) may be most critical for responses to monovalent antigens (Noviski and Zikherman, 2018Noviski M. Zikherman J. Control of autoreactive B cells by IgM and IgD B cell receptors: maintaining a fine balance.Curr. Opin. Immunol. 2018; 55: 67-74Crossref PubMed Scopus (0) Google Scholar). Tyrosine phosphorylation leads to a cascade of downstream signaling events including the activation of multiple pathways. In addition, CD19 associates with IgM and IgD and is involved primarily in triggering the PI3 kinase-Akt pathway (Kurosaki et al., 2010Kurosaki T. Shinohara H. Baba Y. B cell signaling and fate decision.Annu. Rev. Immunol. 2010; 28: 21-55Crossref PubMed Scopus (189) Google Scholar). Together, signals transduced downstream of the BCR complex lead to changes in the expression of numerous genes, including upregulation of costimulatory molecules (CD86, CD80), adhesion molecules (ICAM1), migration receptors, pro-survival molecules, and cell-cycle-related genes. Most complex antigens will engage other receptors on the B cell in addition to the BCR. The ligation of some co-receptors, such as toll-like receptors (TLRs) or complement receptors (CR2), leads to amplification and possibly qualitative modification in the BCR signal (Carroll and Isenman, 2012Carroll M.C. Isenman D.E. Regulation of humoral immunity by complement.Immunity. 2012; 37: 199-207Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar, Suthers and Sarantopoulos, 2017Suthers A.N. Sarantopoulos S. TLR7/TLR9- and B Cell Receptor-Signaling Crosstalk: Promotion of Potentially Dangerous B Cells.Front. Immunol. 2017; 8: 775Crossref PubMed Scopus (5) Google Scholar). Co-receptor engagement may also reduce the threshold of antigen needed to activate B cells. Conversely, B cells express multiple ITIM-containing receptors that recruit negative regulatory phosphatases, such as SHIP1 and SHP1, and these dampen the BCR signal (Tsubata, 2018Tsubata T. Ligand Recognition Determines the Role of Inhibitory B Cell Co-receptors in the Regulation of B Cell Homeostasis and Autoimmunity.Front. Immunol. 2018; 9: 2276Crossref PubMed Scopus (0) Google Scholar). For example, FcγRIIb contributes to antibody-mediated negative feedback of B cell activation by recruiting SHIP1 to the BCR. CD22, a member of the sialic acid binding Ig-type lectin (Siglec) family, restrains tonic and antigen-induced BCR signaling in a gene-dosage sensitive and SHP1-dependent manner. CD72 recognizes the lupus self-antigen Sm/RNP and limits autoreactive B cell activation by recruitment of SHP1 to the BCR (Tsubata, 2018Tsubata T. Ligand Recognition Determines the Role of Inhibitory B Cell Co-receptors in the Regulation of B Cell Homeostasis and Autoimmunity.Front. Immunol. 2018; 9: 2276Crossref PubMed Scopus (0) Google Scholar). BCR triggering also prompts internalization of the BCR and bound antigen in a predominantly clathrin-dependent manner. Internalization requires tyrosine-containing motifs in Igα and Igβ and involves SFK activity (Hoogeboom and Tolar, 2016Hoogeboom R. Tolar P. Molecular Mechanisms of B Cell Antigen Gathering and Endocytosis.Curr. Top. Microbiol. Immunol. 2016; 393: 45-63PubMed Google Scholar). Uptake of membrane bound antigens can involve an actin-dependent membrane “spreading and gathering” process prior to internalization. Forces generated by myosin during invagination can lead to rupture of weak bonds between BCR and antigen and may serve as a form of affinity discrimination (Hoogeboom and Tolar, 2016Hoogeboom R. Tolar P. Molecular Mechanisms of B Cell Antigen Gathering and Endocytosis.Curr. Top. Microbiol. Immunol. 2016; 393: 45-63PubMed Google Scholar). After internalization, antigen travels via endosomes to lysosomes for enzymatic processing, and peptides are docked on MHC class II for delivery to the cell surface and presentation to T cells. For the B cell response to progress, proliferation has to occur (Figure 2). This is necessary for the generation of a clonal population of daughter cells, but also for differentiation. Antigens of low valency trigger B cell transition from G0 to G1 of the cell cycle, poising the cell for rapid proliferation in response to helper T cell-derived signals in T-dependent responses. In some cases, when signaling via co-receptors (such as TLRs) is strong, the need for T cell help may be overcome. This is designated a T-independent type 1 response. Alternatively, highly multivalent antigens alone may trigger sufficiently strong BCR signaling for cells to enter into cycle, in a T-independent type 2 response. These T-independent events can be augmented by cytokines such as BAFF and APRIL (TNFSF13), derived from innate sensor-engaged accessory cells (Balázs et al., 2002Balázs M. Martin F. Zhou T. Kearney J. Blood dendritic cells interact with splenic marginal zone B cells to initiate T-independent immune responses.Immunity. 2002; 17: 341-352Abstract Full Text Full Text PDF PubMed Scopus (471) Google Scholar). Following BCR engagement, co-receptor activation, T cell help, and/or cytokine signals, cell division is coupled with subsequent differentiation events. For example, in vitro studies have established that class switch recombination (CSR) to other BCR isotypes, and B cell differentiation into plasma cells, require a minimum number of cell divisions (Nutt et al., 2015Nutt S.L. Hodgkin P.D. Tarlinton D.M. Corcoran L.M. The generation of antibody-secreting plasma cells.Nat. Rev. Immunol. 2015; 15: 160-171Crossref PubMed Scopus (323) Google Scholar). In T-dependent immune responses, rare antigen-engaged B cells must encounter rare cognate antigen-specific T cells (Figure 2). One early consequence of BCR triggering is the upregulation of CCR7 and EBI2, with these chemoattractant receptors acting together to guide B cells to the interface of the B cell follicle and the T cell zone (Cyster et al., 2014Cyster J.G. Dang E.V. Reboldi A. Yi T. 25-Hydroxycholesterols in innate and adaptive immunity.Nat. Rev. Immunol. 2014; 14: 731-743Crossref PubMed Scopus (117) Google Scholar). Another effect is downregulation of S1PR1 to ensure that the activated cells are retained in the responding tissue. At the follicle-T zone interface, B cells interact with CD4 helper T cells, the latter often (but not always) pre-activated by encounter with antigen-presenting dendritic cells (DCs), and they engage in interactions that last tens of minutes and sometimes more than an hour (Allen et al., 2007Allen C.D. Okada T. Cyster J.G. Germinal-center organization and cellular dynamics.Immunity. 2007; 27: 190-202Abstract Full Text Full Text PDF PubMed Scopus (543) Google Scholar, Hong et al., 2018Hong S. Zhang Z. Liu H. Tian M. Zhu X. Zhang Z. Wang W. Zhou X. Zhang F. Ge Q. et al.B Cells Are the Dominant Antigen-Presenting Cells that Activate Naive CD4(+) T Cells upon Immunization with a Virus-Derived Nanoparticle Antigen.Immunity. 2018; 49: 695-708Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Qi et al., 2014Qi H. Kastenmüller W. Germain R.N. Spatiotemporal basis of innate and adaptive immunity in secondary lymphoid tissue.Annu. Rev. Cell Dev. Biol. 2014; 30: 141-167Crossref PubMed Scopus (62) Google Scholar). Multiple interaction partners guide and shape the nature of cognate B-T interactions. Integrins are important players in most leukocyte cell-cell interactions and migration and contribute to the stability of B-T interactions. The integrin LFA1 on helper T cells engages both ICAM1 and ICAM2 on B cells and augments the ability of lower affinity B cells to enter into responses (Zaretsky et al., 2017Zaretsky I. Atrakchi O. Mazor R.D. Stoler-Barak L. Biram A. Feigelson S.W. Gitlin A.D. Engelhardt B. Shulman Z. ICAMs support B cell interactions with T follicular helper cells and promote clonal selection.J. Exp. Med. 2017; 214: 3435-3448Crossref PubMed Scopus (14) Google Scholar). The amount of MHC-peptide presented on the B cell also contributes to the stability of these interactions (Zaretsky et al., 2017Zaretsky I. Atrakchi O. Mazor R.D. Stoler-Barak L. Biram A. Feigelson S.W. Gitlin A.D. Engelhardt B. Shulman Z. ICAMs support B cell interactions with T follicular helper cells and promote clonal selection.J. Exp. Med. 2017; 214: 3435-3448Crossref PubMed Scopus (14) Google Scholar). Actin regulatory proteins are important, and some of the B cell response defects arising from deficiency in Wiskott-Aldrich syndrome protein (WASp), WASp interacting protein (WIP), various Rho GTPases, or the guanidine exchange factors (GEFs) DOCK8 and intersectin-2 (ITSN2), might be a consequence of reduced B-T conjugate stability (Burbage et al., 2018Burbage M. Gasparrini F. Aggarwal S. Gaya M. Arnold J. Nair U. Way M. Bruckbauer A. Batista F.D. Tuning of in vivo cognate B-T cell interactions by Intersectin 2 is required for effective anti-viral B cell immunity.eLife. 2018; 7: e26556Crossref PubMed Scopus (6) Google Scholar). Costimulatory signaling from CD86 to CD28 is also crucial in the early phase of B cell responses. B cells that have received T cell help may undergo a variety of differentiation states described in Figure 2, including the formation of germinal centers (GCs). Ongoing B-T interactions are critical for the maintenance of GCs. In a GC response, ICOSL engagement of ICOS, a relative of CD28, becomes more important. SLAM family molecules (in particular SLAM, CD84, and Ly108) undergo homotypic interactions between T follicular helper (Tfh) cells and B cells. When T cells lack the SLAM-associated protein, SAP, SLAM molecules recruit SHP1 in an unrestrained way and this antagonizes the ability of Tfh cells to support the GC response (Cannons et al., 2011Cannons J.L. Tangye S.G. Schwartzberg P.L. SLAM family receptors and SAP adaptors in immunity.Annu. Rev. Immunol. 2011; 29: 665-705Crossref PubMed Scopus (280) Google Scholar, Crotty, 2014Crotty S. T follicular helper cell differentiation, function, and roles in disease.Immunity. 2014; 41: 529-542Abstract Full Text Full Text PDF PubMed Scopus (611) Google Scholar). The function of SLAM family homotypic interactions under SAP replete conditions have been difficult to unravel (Chen et al., 2017Chen S. Cai C. Li Z. Liu G. Wang Y. Blonska M. Li D. Du J. Lin X. Yang M. Dong Z. Dissection of SAP-dependent and SAP-independent SLAM family signaling in NKT cell development and humoral immunity.J. Exp. Med. 2017; 214: 475-489Crossref PubMed Scopus (12) Google Scholar, Hu et al., 2016Hu J.K. Crampton J.C. Locci M. Crotty S. CRISPR-Mediated Slamf1Δ/Δ Slamf5Δ/Δ Slamf6Δ/Δ Triple Gene Disruption Reveals NKT Cell Defects but Not T Follicular Helper Cell Defects.PLoS ONE. 2016; 11: e0156074PubMed Google Scholar, Huang et al., 2016Huang B. Gomez-Rodriguez J. Preite S. Garrett L.J. Harper U.L. Schwartzberg P.L. CRISPR-Mediated Triple Knockout of SLAMF1, SLAMF5 and SLAMF6 Supports Positive Signaling Roles in NKT Cell Development.PLoS ONE. 2016; 11: e0156072PubMed Google Scholar), but the pathway can contribute to interleukin (IL)-4 induction in Tfh cells (Yusuf et al., 2010Yusuf I. Kageyama R. Monticelli L. Johnston R.J. Ditoro D. Hansen K. Barnett B. Crotty S. Germinal center T follicular helper cell IL-4 production is dependent on signaling lymphocytic activation molecule receptor (CD150).J. Immunol. 2010; 185: 190-202Crossref PubMed Scopus (244) Google Scholar). PD1 is highly expressed on Tfh cells, and both PDL1 and PDL2 can be expressed on B cells, with PDL1 being constitutively present. The PDL1-PD1 interaction appears to exert a restraining influence on GC B cells because intrinsic deficiency in PDL1 gives GC B cells a competitive advantage (Shi et al., 2018Shi J. Hou S. Fang Q. Liu X. Liu X. Qi H. PD-1 Controls Follicular T Helper Cell Positioning and Function.Immunity. 2018; 49: 264-274Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar). A crucial component of T cell help is the expression of CD40L and engagement of B cell CD40. CD40L, a member of the tumor necrosis factor (TNF) family, is expressed on T cells as a membrane homotrimer, and its surface expression is upregulated following T cell activation. CD40 is constitutively expressed on mature B cells, including naive and GC B cells. Within GCs, the surface area of interaction (or entanglement) of GC B cells and Tfh cells is increased by ICOSL-ICOS signaling. ICOSL is upregulated on mouse GC B cells by CD40 signaling in a positive feedback loop (Liu et al., 2015Liu D. Xu H. Shih C. Wan Z. Ma X. Ma W. Luo D. Qi H. T-B-cell entanglement and ICOSL-driven feed-forward regulation of germinal centre reaction.Nature. 2015; 517: 214-218Crossref PubMed Scopus (142) Google Scholar). In humans, CD40 was not found to augment ICOSL expression on GC B cells. Instead, dopamine was discovered as a novel Tfh cell-secreted factor that augments ICOSL on human GC B cells via dopamine receptor 1 (DRD1). Imaging studies using supported lipid bilayers revealed that ICOS ligation augmented CD40L accumulation at the synaptic cleft in human T cells (Papa et al., 2017Papa I. Saliba D. Ponzoni M. Bustamante S. Canete P.F. Gonzalez-Figueroa P. McNamara H.A. Valvo S. Grimbaldeston M. Sweet R.A. et al.TFH-derived dopamine accelerates productive synapses in germinal centres.Nature. 2017; 547: 318-323Crossref PubMed Scopus (38) Google Scholar). The extent of CD40L-CD40 engagement is thought to impact on the fate decisions of B cells at various stages of differentiation in the context of other extrinsic signals (Ise et al., 2018Ise W. Fujii K. Shiroguchi K. Ito A. Kometani K. Takeda K. Kawakami E. Yamashita K. Suzuki K. Okada T. et al.T Follicular Helper Cell-Germinal Center B Cell Interaction Strength Regulates Entry into Plasma Cell or Recycling Germinal Center Cell Fate.Immunity. 2018; 48: 702-715Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, Zhou et al., 2018Zhou J.H.S. Markham J.F. Duffy K.R. Hodgkin P.D. Stochastically Timed Competition Between Division and Differentiation Fates Regulates the Transition From B Lymphoblast to Plasma Cell.Front. Immunol. 2018; 9: 2053Crossref PubMed Scopus (0) Google Scholar). Tfh cells are also known to secrete cytokines that profoundly influence B cells. Two of the major cytokines secreted by Tfh cells are IL-4 and IL-21 (Crotty, 2014Crotty S. T follicular helper cell differentiation, function, and roles in disease.Immunity. 2014; 41: 529-542Abstract Full Text Full Text PDF PubMed Scopus (611) Google Scholar, Vinuesa et al., 2016Vinuesa C.G. Linterman M.A. Yu D. MacLennan I.C. Follicular Helper T Cells.Annu. Rev. Immunol. 2016; 34: 335-368Crossref PubMed Scopus (282) Google Scholar). These cytokines promote B cell proliferation, CSR, and differentiation into plasma cells or GC B cells (Moens and Tangye, 2014Moens L. Tangye S.G. Cytokine-Mediated Regulation of Plasma Cell Generation: IL-21 Takes Center Stage.Front. Immunol. 2014; 5: 65Crossref PubMed Scopus (65) Google Scholar, Vinuesa et al., 2016Vinuesa C.G. Linterman M.A. Yu D. MacLennan I.C. Follicular Helper T Cells.Annu. Rev. Immunol. 2016; 34: 335-368Crossref PubMed Scopus (282) Google Scholar). Both IL-4 and IL-21 receptors signal through the common cytokine γ chain, yet are coupled to different STAT proteins that enables the regulation of distinct subsets of genes (Lin and Leonard, 2018Lin J.X. Leonard W.J. The Common Cytokine Receptor γ Chain Family of Cytokines.Cold Spring Harb. Perspect. Biol. 2018; 10: a028449Crossref PubMed Scopus (5) Google Scholar). Indeed, studies in gene-targeted mice indicate tha" @default.
• W2938678047 created "2019-04-25" @default.
• W2938678047 creator A5014072057 @default.
• W2938678047 creator A5061559047 @default.
• W2938678047 date "2019-04-01" @default.
• W2938678047 modified "2023-10-17" @default.
• W2938678047 title "B Cell Responses: Cell Interaction Dynamics and Decisions" @default.
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