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Mature B cells coexpress both IgM and IgD B-cell antigen receptor (BCR) classes, which are organized on the cell surface in distinct protein islands. The specific role of the IgD–BCR is still enigmatic, but it is colocalized with several other receptors on the B-cell surface, including the coreceptor CD19. Here, we report that the chemokine receptor CXCR4 is also found in proximity to the IgD–BCR. Furthermore, B cells from IgD-deficient mice show defects in CXCL12-mediated CXCR4 signaling and B-cell migration, whereas B cells from IgM-deficient mice are normal in this respect. CXCR4 activation results in actin cytoskeleton remodeling and PI3K/Akt and Erk signaling in an IgD–BCR-dependent manner. The defects in CXCR4 signaling in IgD-deficient B cells can be overcome by anti-CD19 antibody stimulation that also increases CXCL12-mediated B-cell migration of normal B cells. These results show that the IgD–BCR, CD19, and CXCR4 are not only colocalized at nanometer distances but are also functionally connected, thus providing a unique paradigm of receptor signaling cross talk and function.

Human IgM + B cells vary in their surface levels of IgD, with the major circulating population of IgM + IgD + cells and a minor population (< 5%) of IgM + IgD − cells. In contrast, in gut-associated lymphoid tissue (GALT) derived from individuals undergoing tonsillectomy or appendectomy, IgM + IgD − B cells constitute ~ 30% of B cells. IgM + IgD − cells isolated from both tonsil and appendix lack plasma cell and B1 cell markers, and approximately 50% express the memory marker CD27. Functionally, GALT IgM + IgD − cells spontaneously secrete IgM, and class-switch to IgA in response to both T-dependent and T-independent stimulation ex-vivo. Immune repertoire profiling reveals that GALT IgM + IgD − cells exhibit lower levels of VH4-34 rearrangements, higher levels of somatic hypermutation, shorter CDR3 sequences and greater clonal overlap with switch memory cells than IgM + IgD + cells. Furthermore, clonal lineage analysis reveals that IgM + IgD − clones can include class-switched sequence variants. These findings suggest a maturational scheme starting from CD27 − IgM + IgD + B cells to CD27 + IgM + IgD + , and then to CD27 − IgM + IgD − , and finally to CD27 + IgM + IgD − B cells. In sum, IgM + IgD − B cells in the mucosa have memory features, give rise to class-switched memory B cells and antibody-secreting cells, and likely contribute significantly to the IgA repertoire in human GALT.

Upon infection, B-lymphocytes expressing antibodies specific for the intruding pathogen develop clonal responses triggered by pathogen recognition via the B-cell receptor. The constant region of antibodies produced by such responding clones dictates their functional properties. In teleost fish, the clonal structure of B-cell responses and the respective contribution of the three isotypes IgM, IgD and IgT remain unknown. The expression of IgM and IgT are mutually exclusive, leading to the existence of two B-cell subsets expressing either both IgM and IgD or only IgT. Here, we undertook a comprehensive analysis of the variable heavy chain (VH) domain repertoires of the IgM, IgD and IgT in spleen of homozygous isogenic rainbow trout (Onchorhynchus mykiss) before, and after challenge with a rhabdovirus, the Viral Hemorrhagic Septicemia Virus (VHSV), using CDR3-length spectratyping and pyrosequencing of immunoglobulin (Ig) transcripts. In healthy fish, we observed distinct repertoires for IgM, IgD and IgT, respectively, with a few amplified μ and τ junctions, suggesting the presence of IgM- and IgT-secreting cells in the spleen. In infected animals, we detected complex and highly diverse IgM responses involving all VH subgroups, and dominated by a few large public and private clones. A lower number of robust clonal responses involving only a few VH were detected for the mucosal IgT, indicating that both IgM(+) and IgT(+) spleen B cells responded to systemic infection but at different degrees. In contrast, the IgD response to the infection was faint. Although fish IgD and IgT present different structural features and evolutionary origin compared to mammalian IgD and IgA, respectively, their implication in the B-cell response evokes these mouse and human counterparts. Thus, it appears that the general properties of antibody responses were already in place in common ancestors of fish and mammals, and were globally conserved during evolution with possible functional convergences.

The establishment of a diverse B cell antigen receptor (BCR) repertoire by V(D)J recombination also generates autoreactive B cells. Anergy is one tolerance mechanism; it renders autoreactive B cells insensitive to stimulation by self-antigen, whereas Toll-like receptor (TLR) signaling can reactivate anergic B cells. Here, we describe a critical role of the transcription factor Ikaros in controlling BCR anergy and TLR signaling. Mice with specific deletion of Ikaros in mature B cells developed systemic autoimmunity. Ikaros regulated many anergy-associated genes, including Zfp318 , which is implicated in the attenuation of BCR responsiveness by promoting immunoglobulin D expression in anergic B cells. TLR signaling was hyperactive in Ikaros-deficient B cells, which failed to upregulate feedback inhibitors of the MyD88–nuclear factor κB signaling pathway. Systemic inflammation was lost on expression of a non-self-reactive BCR or loss of MyD88 in Ikaros-deficient B cells. Thus, Ikaros acts as a guardian preventing autoimmunity by promoting BCR anergy and restraining TLR signaling. Immature B cells expressing self-reactive BCRs induce anergy programs to promote tolerance. Busslinger and colleagues show that the transcription factor Ikaros enforces anergy by inducing transcription of negative-feedback regulators of the BCR and TLR–MyD88 pathways.

Significance Human IgM ⁺IgD ⁺CD27 ⁺ B lymphocytes represent a large subpopulation of the human B-cell pool, but their generation is debated and their immunological functions are poorly understood. This work shows that these lymphocytes possess typical memory B-cell expression patterns, enabling them to differentiate rapidly into plasma cells upon restimulation. Moreover, we reveal unique features of these IgM memory B cells, their potential to reenter germinal center reactions, and their specific interaction with immunomodulatory neutrophils in early inflammatory responses. Thus, key characteristics and functions of a major human B-cell subset are elucidated. The generation and functions of human peripheral blood (PB) IgM ⁺IgD ⁺CD27 ⁺ B lymphocytes with somatically mutated IgV genes are controversially discussed. We determined their differential gene expression to naive B cells and to IgM-only and IgG ⁺ memory B cells. This analysis revealed a high similarity of IgM ⁺(IgD ⁺)CD27 ⁺ and IgG ⁺ memory B cells but also pointed at distinct functional capacities of both subsets. In vitro analyses revealed a tendency of activated IgM ⁺IgD ⁺CD27 ⁺ B cells to migrate to B-cell follicles and undergo germinal center (GC) B-cell differentiation, whereas activated IgG ⁺ memory B cells preferentially showed a plasma cell (PC) fate. This observation was supported by reverse regulation of B-cell lymphoma 6 and PR domain containing 1 and differential BTB and CNC homology 1, basic leucine zipper transcription factor 2 expression. Moreover, IgM ⁺IgD ⁺CD27 ⁺ B lymphocytes preferentially responded to neutrophil-derived cytokines. Costimulation with catecholamines, carcinoembryonic antigen cell adhesion molecule 8 (CEACAM8), and IFN-γ caused differentiation of IgM ⁺IgD ⁺CD27 ⁺ B cells into PCs, induced class switching to IgG ₂, and was reproducible in cocultures with neutrophils. In conclusion, this study substantiates memory B-cell characteristics of human IgM ⁺IgD ⁺CD27 ⁺ B cells in that they share typical memory B-cell transcription patterns with IgG ⁺ post-GC B cells and show a faster and more vigorous restimulation potential, a hallmark of immune memory. Moreover, this work reveals a functional plasticity of human IgM memory B cells by showing their propensity to undergo secondary GC reactions upon reactivation, but also by their special role in early inflammation via interaction with immunomodulatory neutrophils.

Colorectal cancer (CRC) is the third most prevalent cancer and understanding its tumor microenvironment (TME) is crucial for the development of innovative therapies. Despite the presence of B cells in CRC infiltrate, their clinical significance is poorly understood. In this study, we observed an enrichment of double-negative (DN) B cells, a subset lacking surface IgD and CD27, in CRC biopsies. Typically underrepresented in physiological conditions, DN B cells expand in certain chronic infections, autoimmune diseases, and cancers. Within this subpopulation, low CD21 expression—a phenotypic hallmark of exhaustion—was observed. Consistently, DN B cells displayed low metabolic activity. Accordingly, total B cells infiltrating CRC tissues showed a diminished capacity to differentiate into antibody-secreting cells (ASCs) upon stimulation. In the murine setting, CRC organoids decreased the frequency of ASCs in co-cultured B cells and induced metabolic dysfunction, marked by altered glucose and fatty acid uptake and dysregulated expression of key metabolic proteins. Moreover, B cells displayed reduced glycolysis and mitochondrial respiration, despite increased mitochondrial dependence. This study provides evidence for DN B cell accumulation within CRC infiltrate and metabolic reprogramming of B cells, suggesting that targeting B cell metabolism may represent a promising strategy to potentiate anti-tumor immune responses.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare lymphoma of B-cell origin with frequent expression of functional B-cell receptors (BCRs). Here we report that expression cloning followed by antigen screening identifies DNA-directed RNA polymerase beta’ (RpoC) from Moraxella catarrhalis as frequent antigen of BCRs of IgD + LP cells. Patients show predominance of HLA-DRB1*04/07 and the IgVH genes encode extraordinarily long CDR3s. High-titer, light-chain-restricted anti-RpoC IgG1/κ-type serum-antibodies are additionally found in these patients. RpoC and MID/hag, a superantigen co-expressed by Moraxella catarrhalis that is known to activate IgD + B cells by binding to the Fc domain of IgD, have additive activation effects on the BCR, the NF-κB pathway and the proliferation of IgD + DEV cells expressing RpoC-specific BCRs. This suggests an additive antigenic and superantigenic stimulation of B cells with RpoC-specific IgD + BCRs under conditions of a permissive MHC-II haplotype as a model of NLPHL lymphomagenesis, implying future treatment strategies. Nodular lymphocyte-predominant Hodgkin lymphoma with IgD+ lymphocyte-predominant (LP) cells is a rare clinical distinct lymphoma subset of B-cell origin. Here the authors show that antigens expressed by Moraxella catarrhalis are recognized by B cell receptors of IgD+ LP cells, suggesting the contribution of chronic antigen stimulation to lymphomagenesis.

Immature B cells are subject to tolerance mechanisms that prevent the expression of self-reactive BCRs. Minguet and colleagues identify the membrane protein caveolin-1 as a regulator of BCR spatial organization and signaling that enforces B cell tolerance. Caveolin-1 (Cav1) regulates the nanoscale organization and compartmentalization of the plasma membrane. Here we found that Cav1 controlled the distribution of nanoclusters of isotype-specific B cell antigen receptors (BCRs) on the surface of B cells. In mature B cells stimulated with antigen, the immunoglobulin M BCR (IgM-BCR) gained access to lipid domains enriched for GM1 glycolipids, by a process that was dependent on the phosphorylation of Cav1 by the Src family of kinases. Antigen-induced reorganization of nanoclusters of IgM-BCRs and IgD-BCRs regulated BCR signaling in vivo . In immature Cav1-deficient B cells, altered nanoscale organization of IgM-BCRs resulted in a failure of receptor editing and a skewed repertoire of B cells expressing immunoglobulin-μ heavy chains with hallmarks of poly- and auto-reactivity, which ultimately led to autoimmunity in mice. Thus, Cav1 emerges as a cell-intrinsic regulator that prevents B cell–induced autoimmunity by means of its role in plasma-membrane organization.

Although initially described as an immune-privileged site, the central nervous system (CNS) is now known to harbor a resident immune system, composed of different innate and adaptive cell types that maintain tissue homeostasis, are regulated in pathological conditions or brain injury and are in connection with the peripheral immune system. However, information regarding a characterization of the B cell subsets colonizing the CNS or their precise role is very scarce in mammals and even more in fish. Teleost fish exclusively express IgM, IgD and the teleost-specific IgT and their expression patterns in B cells define diverse B cell subsets. IgM is the main Ig isotype in systemic responses, while previous evidence suggested a mucosally dedicated role for IgT. Recent work by our group and others, also pointed to a role for IgD in maintaining mucosal homeostasis. However, in the current study, we demonstrate through different techniques that IgD + and IgT + expressing B cells are predominant in the teleost CNS, albeit a very different distribution. Additionally, B cell receptor (BCR) repertoire analysis pointed to both populations as antigen-experienced. Further research is needed to fully elucidate the specific roles of IgT and IgD in the teleost brain, but this discovery opens exciting avenues for future investigations in the fields of immunology and neuroscience.

B cells exclusively expressing IgD on the cell surface (IgD + IgM − B cells) have been identified in mammals, where they seem to play a still not well-defined role in peripheral tolerance. These cells have also been reported in catfish ( Ictalurus punctatus ) peripheral blood and in several mucosal tissues of rainbow trout ( Oncorhynchus mykiss ), including gut, gills and skin. As in mammals, the precise function of these cells remains obscure, yet, in rainbow trout mucosal surfaces, these cells have been shown to be differentiated to plasma-like cells. Interestingly, in the gills, these IgD + IgM − B cells expressed high levels of the CC chemokine receptor 7 (CCR7), receptor that in mammals controls the migration of B and T cells to secondary lymphoid organs. In this work, we have established that this is also true for the trout skin, where CCR7 defines a specific subset of IgD + IgM − B cells that are further differentiated to a plasma-like profile than those not expressing CCR7. These findings increase the current understanding of this enigmatic B cell population and point to CCR7 as a key differentiation marker for these cells.