A self-sustaining layer of early-life-origin B cells drives steady-state IgA responses in the adult gut
Stefano VerganiKonjit Getachew MuletaClément Da SilvaAlexander DoyleTrine A. KristiansenSelene SodiniNiklas KrausseGiorgia MontanoKnut KotarskyJoy NakawesiHugo ÅkerstrandStijn VanheeSneh Lata GuptaDavid BryderWilliam W. AgaceKatharina LahlJoan Yuan
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The adult immune system consists of cells that emerged at various times during ontogeny. We aimed to define the relationship between developmental origin and composition of the adult B cell pool during unperturbed hematopoiesis. Lineage tracing stratified murine adult B cells based on the timing of output, revealing that a substantial portion originated within a restricted neonatal window. In addition to B-1a cells, early-life time-stamped B cells included clonally interrelated IgA plasma cells in the gut and bone marrow. These were actively maintained by B cell memory within gut chronic germinal centers and contained commensal microbiota reactivity. Neonatal rotavirus infection recruited recurrent IgA clones that were distinct from those arising by infection with the same antigen in adults. Finally, gut IgA plasma cells arose from the same hematopoietic progenitors as B-1a cells during ontogeny. Thus, a complex layer of neonatally imprinted B cells confer unique antibody responses later in life.Keywords:
Immunoglobulin A
Abstract The peripheral B cell compartment contains high levels of “polyreactivity” including autospecificities. We have described a pathway that certain autoreactive B cells may take in gaining stable access to the foreign Ag-responsive peripheral compartment. This pathway was revealed in mice expressing a targeted Ig H chain transgene encoding BCRs with “multireactivity” for the hapten arsonate and DNA-based autoantigens. B cells expressing such BCRs develop to mature follicular phenotype and locale, and are not short-lived. These B cells express very low levels of BCR, indicating that they are not “ignorant” of self Ag, but do not display features of anergy in in vitro assays. Nonetheless, a variety of states of lymphocyte anergy has been described, and some may only be manifested in vivo. As such, we analyzed the ability of these B cells to participate in a T cell-dependent immune response to arsonate in vivo. These B cells mount an early primary response similar to control B cells, including homing to follicles, migration to the T-B interface, and induction of costimulatory molecules, proliferation, differentiation to AFCs, class switching, and entry into GCs and somatic hypermutation. Nonetheless, these B cells display reduced participation in the latter stages of the GC response and in the anamnestic AFC response. In total, these data suggest that while the autoreactivity of this type of B cell does not result in anergy, the ability of such B cells to participate in a cross-reactive immune response to foreign Ag is compromised.
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The IRF and Ets families of transcription factors regulate the expression of a range of genes involved in immune cell development and function. However, the understanding of the molecular mechanisms of each family member has been limited due to their redundancy and broad effects on multiple lineages of cells. Here, we report that double deletion of floxed Irf8 and Spi1 (encoding PU.1) by Mb1-Cre (designated DKO mice) in the B cell lineage resulted in severe defects in the development of follicular and germinal center (GC) B cells. Class-switch recombination and antibody affinity maturation were also compromised in DKO mice. RNA-seq (sequencing) and ChIP-seq analyses revealed distinct IRF8 and PU.1 target genes in follicular and activated B cells. DKO B cells had diminished expression of target genes vital for maintaining follicular B cell identity and GC development. Moreover, our findings reveal that expression of B-cell lymphoma protein 6 (BCL6), which is critical for development of germinal center B cells, is dependent on IRF8 and PU.1 in vivo, providing a mechanism for the critical role for IRF8 and PU.1 in the development of GC B cells.
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BOB.1/OBF.1 is a lymphocyte-specific transcriptional co-activator of octamer-dependent transcription. It regulates the expression of genes important for lymphocyte physiology together with the Oct-1 and Oct-2 transcription factors. So far, BOB.1/OBF.1 has been studied in conventional knockout mice, whereby a function of BOB.1/OBF.1 in B but also in T cells was described. The main characteristic of BOB.1/OBF.1-deficient mice is the complete absence of germinal centers. However, it is entirely unsolved at which stage of B-cell development BOB.1/OBF.1 expression is essential for germinal center formation. Still, it is not known whether defects observed late in B-cell development of BOB.1/OBF.1-deficient mice are merely a consequence of defective early B-cell development. To answer the question, whether BOB.1/OBF.1 expression is required before or during the process of germinal center formation, we established a mouse system, which allows the conditional deletion of BOB.1/OBF.1 at different stages of B-cell development. Our data reveal a requirement for BOB.1/OBF.1 during both early antigen-independent and late antigen-dependent B-cell development, and further a requirement for efficient germinal center reaction during complete B-cell ontogeny. By specifically deleting BOB.1/OBF.1 in germinal center B cells, we provide evidence that the failure to form germinal centers is a germinal center B-cell intrinsic defect and not exclusively a consequence of defective early B-cell maturation.
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Germinal centers (GCs) are specialized structures in which B lymphocytes undergo clonal expansion, class switch recombination, somatic hypermutation, and affinity maturation. Although these structures were previously thought to contain a limited number of isolated B cell clones, recent in vivo imaging studies revealed that they are in fact dynamic and appear to be open to their environment. We demonstrate that B cells can colonize heterologous GCs. Invasion of primary GCs after subsequent immunization is most efficient when T cell help is shared by the two immune responses; however, it also occurs when the immune responses are entirely unrelated. We conclude that GCs are dynamic anatomical structures that can be reutilized by newly activated B cells during immune responses.
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IL-21 produced by follicular Th (Tfh) cells is an important regulator of Tfh cell development and B cell responses, including germinal center (GC) formation. However, whether defective GC formation and Ab responses are a consequence of impaired Tfh cells development or a B cell-intrinsic defect in IL-21-deficient mice requires clarification. To address this question, we generated chimeric mice lacking IL-21R exclusively on B cells. In this study, we demonstrate that GC reaction and B cell responses induced by immunization with virus-like particles were strongly reduced in both global and B cell-specific IL-21R-deficient mice. Interestingly, the presence of TLR7 ligand within virus-like particles largely restored defective GC reaction and Ab responses in global as well as in B cell-specific IL-21R-deficient mice. Hence, IL-21 acts directly on B cells and cooperates with TLR signaling for optimal B cell responses.
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ABSTRACT Rho family GTPases are critical for normal B cell development and function and their activity is regulated by a large and complex network of guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). However, the role of GAPs in B cell development is poorly understood. Here we show that the novel Rac-GAP ARHGAP25 is important for B cell development in mice in a CXCR4-dependent manner. We show that Arhgap25 deficiency leads to a significant decrease in peripheral blood B cell numbers, as well as defects in mature B cell differentiation. Arhgap25 -/- B cells respond to antigen stimulation in vitro and in vivo but have impaired germinal center formation and decreased IgG1 class switching. Additionally, Arhgap25 -/- B cells exhibit increased chemotaxis to CXCL12. Taken together, these studies demonstrate an important role for Arhgap 25 in peripheral B cell development and antigen response.
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Abstract Antigen-reactive B cells in the spleen of mice immunized with T cell-dependent antigens generate antibody-producing foci in periarteriolar lymphoid sheaths (PALS) or migrate into follicles to form germinal centers. Germinal center B cells clonally expand, have somatic hypermutation in IgV-region genes, are selected by apoptosis on the basis of antigen-specific signals, and differentiate to memory B cells. Two transcription factors (Bcl6 and c-Fos) in B cells play a critical role in the development of germinal centers. (1) Bcl6 is highly expressed in germinal center B cells, and defects in B cells perturb the formation of germinal centers but not that of PALS-associated foci, indicating the essential role of Bcl6 in the differentiation. (2) Overexpression of c-Fos in germinal center B cells induces apoptosis and perturbs the formation of memory B cells. Overexpression of Bcl-2 cannot rescue c-Fos-induced apoptosis in germinal center B cells. Since c-Fos is induced in mature B cells which have reacted with antigens, and clonal deletion of self-reactive B cells is insensitive to overexpression of Bcl-2, c-Fos may play a causal role in the clonal deletion of germinal center B cells. Thus, these factors provide a unique opportunity to investigate the molecular mechanisms of memory B cell development.
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Abstract BCR engagement drives phosphorylation of the multi-adapter, CARMA1, and assembly of signaling complexes required for NF-κB activation. B cell lymphomas are frequently associated with constitutive NF-κB activation that sustains their survival. At least 10% of germinal center (GC) derived, activated B-cell like diffuse large B-cell lymphomas (ABC-DLBCLs) exhibit gain-of-function mutations in CARMA1. In the current study, we directly assess the impact activated CARMA1 (aCARMA1) on GC biology. We developed a novel mouse model that permits inducible expression of aCARMA1. Following T-dependent immunization, mice with B cell intrinsic aCARMA1 exhibit an expanded plasma cell compartment and reduced GC B cell numbers. A similar phenotype was present with GC restricted aCARMA1 expression, leading to increased total and antigen-specific IgG. ABC-DLBCL tumors frequently exhibit somatic mutations predicted to block terminal B cell differentiation. To better define how aCARMA1 impacts GC biology and cooperates with these lesions, we crossed KI mice to Blimp1F/F mice. aCARMA1 expression, in the absence of Blimp1, lead to increased GC B cell numbers compared to controls. Current studies are focused on detailed analysis of this altered response. Our results demonstrate that aCARMA1 is sufficient to alter the GC response and B cell fate, favoring plasma cell development. Further, in the setting of inability to exit the GC, aCARMA1 may be sufficient to directly promote lymphomagenesis.
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