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Teleost B cells have phagocytic activities for ingesting particulate antigens, such as bacteria, in addition to the functional secretion of immunoglobulins (Igs). In the present study, the phagocytic activities of IgM B cells under various differentiational conditions residing in peripheral blood leukocytes were investigated in a teleost fish Nile tilapia ( ). The IgM B cells were recognized as IgM or IgM subsets based on their membrane IgM (mIgM) levels. The mIgM, secreted IgM (sIgM), major histocompatibility complex class II and reactive oxygen species were detected. Expressions of transcription factors (Pax5 and Blimp-1) and B cell signaling molecules (CD79a, CD79b, BLNK, and LYN) suggested that IgM B cells were resembling as plasma-like cells and IgM resembling as naïve/mature B cells, respectively. Analysis of phagocytic activities demonstrated that both IgM and IgM B cells have a similar phagocytic ability (phagocytosis percentage); however, the phagocytic capacity [phagocytic index and the mean fluorescence intensity (MFI)] of IgM B cells was significantly higher than that of IgM B cells. Taken together, the results indicated that B cell differentiation may cause the decrease of phagocytic capacity but not phagocytic ability of phagocytic IgM B cells in teleost. The finding may provide an evolutionary evidence for understanding the greater specialization of the B cell in more sophisticated adaptive humoral immunity, by decreasing phagocytic activity in order to contribute its function more specifically into antibody-secreting.

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.

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.

Immunoglobulin M (IgM) and IgM + B cells are key components of the humoral immune system, providing defense against pathogen invasion. While the role of IgM in the systemic and mucosal immune responses of fish to parasites and bacteria has been partially investigated, its function in viral infections remains underexplored. This study successfully developed a largemouth bass ( Micropterus salmoides ) model for ranavirus immersion infection. Our findings revealed that viral infection caused significant pathological changes in the gill and head kidney tissues, along with a marked upregulation of adaptive immune gene expression. Interestingly, fish that survived an initial viral infection exhibited minimal mortality and low viral loads in the gill and head kidney tissues when exposed to a higher viral concentration. Notably, in these fish with secondary infections, there was a significant increase in IgM protein levels in both the blood and gill mucus, as well as a pronounced accumulation of IgM + B cells in the gill and head kidney tissues. Additionally, the serum contained high levels of virus-specific IgM, which demonstrated the ability to neutralize the virus. These findings highlight the crucial role of IgM in the immune response to viral infections in largemouth bass and suggest its potential as a target for enhancing viral resistance in aquaculture.

Plasma cells are terminally differentiated antibody-secreting B lymphocytes that contribute to humoral immunity by producing large numbers of antibodies. Increasing evidence suggests that teleost fish B cells share certain characteristics with mammalian B1 B cells, including antibody-secreting, phagocytic, and antigen-presenting capacities. However, the difference between mature B cells and plasma cells remains unclear. In this study, we found that, based on their light-scattering characteristics, tilapia anterior kidney (AK) leukocytes can be categorized into two IgM + B-cell subsets: the lymphoid (L) gate and granulocyte–monocyte/macrophage (G-M) subsets. G-M gate cells are more numerous than L-gate cells and have higher mean fluorescence, but lower forward scatter and side scatter. We analyzed the morphological and ultrastructural features of sorted IgM + cells and found that L-gate IgM + cells have a high nucleus–cytoplasm ratio and lymphocyte-like morphology, whereas G-M gate IgM + cells have a small nucleus, more abundant endoplasmic reticulum, and a larger number of mitochondria, and have a plasma cell-like or macrophage-like morphology. To further characterize the cell types, we examined the specific patterns of expression of B-cell- and T-cell-related genes. We found that B-cell-specific genes were expressed by both L-gate and G-M gate IgM + cells, and that G-M gate IgM + cells secreted extremely high levels of IgM. However, T-cell-related genes were highly expressed only in L-gate IgM – cells. These results suggest that G-M gate IgM + cells are similar to plasma-like cells, with high antibody-secreting capacity. Given that G-M gate cells include the granulocyte, monocyte, and macrophage cell types, but not B cells, monocyte/macrophage markers were used to investigate the cell types further. A macrophage receptor with a collagenous structure was frequently observed, and macrophage-expressed gene-1 was highly expressed, in the G-M gate IgM + cells. Phagocytic capacity, as determined by ingestion of beads or bacteria, was significantly higher in G-M gate IgM + cells than in L-gate IgM + cells, as was antigen-processing capacity. Our findings show that tilapia AK leukocytes can be divided into two IgM + B-cell subsets and that G-M gate IgM + cells resemble plasma-like cells, having high antibody-secreting, phagocytic, and antigen-presenting capacities. Thus, this study increases our understanding of the functions of teleost fish plasma-like cells.

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 ( ) peripheral blood and in several mucosal tissues of rainbow trout ( ), 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.

The interest in dietary amino acids (AAs) as potential immunomodulators has been growing the recent years, since specific AAs are known to regulate key metabolic pathways of the immune response or increase the synthesis of some immune-related proteins. Methionine, tryptophan and lysine are among the ten essential AAs for fish, meaning that they cannot be produced endogenously and must be provided through the diet. To date, although dietary supplementation of fish with some of these AAs has been shown to have positive effects on some innate immune parameters and disease resistance, the effects that these AAs provoke on cells of the adaptive immune system remained unexplored. Hence, in the current study, we have investigated the effects of these three AAs on the functionality of rainbow trout ( Oncorhynchus mykiss ) IgM + B cells. For this, splenic leukocytes were isolated from untreated adult rainbow trout and incubated in culture media additionally supplemented with different doses of methionine, tryptophan or lysine in the presence or absence of the model antigen TNP-LPS (2,4,6-trinitrophenyl hapten conjugated to lipopolysaccharide). The survival, IgM secreting capacity and proliferation of IgM + B cells was then studied. In the case of methionine, the phagocytic capacity of IgM + B cells was also determined. Our results demonstrate that methionine supplementation significantly increases the proliferative effects provoked by TNP-LPS and also up-regulates the number of cells secreting IgM, whereas tryptophan or lysine have either minor or even negative effects on rainbow trout IgM + B cells. This increase in the number of IgM-secreting cells in response to methionine surplus was further verified in a feeding experiment, in which the beneficial effects of methionine on the specific response to anal immunization were also confirmed. The results presented demonstrate the beneficial effects of dietary supplementation with methionine on the adaptive immune responses of fish.

Tumor-infiltrating B cells and tertiary lymphoid structures have been identified to predict the responses to immune checkpoint inhibitors (ICIs) in cancer immunotherapy. Considering the feasibility of sample collection, whether peripheral B cell signatures are associated with the responses to ICI therapy remains unclear. Herein, we have defined peripheral B cell signatures in advanced non-small cell lung cancer (NSCLC) patients receiving anti-PD-1 monotherapy and investigated their associations with clinical efficacy. It was found that the percentages of B cells before the treatment (baseline) were significantly higher ( P = 0.004) in responder (R, n = 17) than those in non-responder (NonR, n = 33) NSCLC patients in a discovery cohort. Moreover, the percentages of baseline IgM + memory B cells were higher ( P < 0.001) in R group than those in NonR group, and associated with a longer progression free survival (PFS) ( P = 0.003). By logistic regression analysis peripheral baseline IgM + memory B cells were identified as an independent prognostic factor ( P = 0.002) for the prediction of the responses to anti-PD-1 monotherapy with the AUC value of 0.791, which was further validated in another anti-PD-1 monotherapy cohort ( P = 0.011, n = 70) whereas no significance was observed in patients receiving anti-PD-L1 monotherapy ( P = 0.135, n = 30). Therefore, our data suggest the roles of peripheral IgM + memory B cells in predicting the responses to anti-PD-1 treatment in Chinese advanced NSCLC patients.

Previous work showed that interferon-λ (IFN-λ) can trigger the synthesis of thymic stromal lymphopoietin (TSLP) by specialized epithelial cells in the upper airways of mice, thereby improving the performance of intranasally administered influenza vaccines. Here we demonstrate that protein-only influenza vaccines containing either IFN-λ or TSLP boosted antigen-specific IgG1 and IgA responses and enhanced the resistance of mice to influenza virus challenge, irrespective of whether the vaccines were applied via the intranasal or the rectal route. TSLP receptor deficiency negatively influenced vaccine-induced antiviral immunity by impairing the migration of dendritic cells from the airways to the draining lymph nodes of immunized mice, thereby restraining follicular helper T cell and germinal center B cell responses. As previously observed during intranasal vaccination, the adjuvant effect of IFN-λ on a rectally administered influenza vaccine was no longer observed when TSLP receptor-deficient mice were used for immunization, highlighting the central role of the IFN-λ/TSLP axis for vaccine-induced antiviral immunity in the mucosa.

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.