Auswahl der wissenschaftlichen Literatur zum Thema „Gut-derived B cells“

The gut microbiota, including bacteria, archaea, fungi, viruses and phages, inhabits the gastrointestinal tract. This commensal microbiota can contribute to the regulation of host immune response and homeostasis. Alterations of the gut microbiota have been found in many immune-related diseases. The metabolites generated by specific microorganisms in the gut microbiota, such as short-chain fatty acids (SCFAs), tryptophan (Trp) and bile acid (BA) metabolites, not only affect genetic and epigenetic regulation but also impact metabolism in the immune cells, including immunosuppressive and inflammatory cells. The immunosuppressive cells (such as tolerogenic macrophages (tMacs), tolerogenic dendritic cells (tDCs), myeloid-derived suppressive cells (MDSCs), regulatory T cells (Tregs), regulatory B cells (Breg) and innate lymphocytes (ILCs)) and inflammatory cells (such as inflammatory Macs (iMacs), DCs, CD4 T helper (Th)1, CD4Th2, Th17, natural killer (NK) T cells, NK cells and neutrophils) can express different receptors for SCFAs, Trp and BA metabolites from different microorganisms. Activation of these receptors not only promotes the differentiation and function of immunosuppressive cells but also inhibits inflammatory cells, causing the reprogramming of the local and systemic immune system to maintain the homeostasis of the individuals. We here will summarize the recent advances in understanding the metabolism of SCFAs, Trp and BA in the gut microbiota and the effects of SCFAs, Trp and BA metabolites on gut and systemic immune homeostasis, especially on the differentiation and functions of the immune cells.

Tryptophan is an essential amino acid from dietary proteins. It can be metabolized into different metabolites in both the gut microbiota and tissue cells. Tryptophan metabolites such as indole-3-lactate (ILA), indole-3-acrylate (IAC), indole-3-propionate (IPA), indole-3-aldehyde (IAID), indoleacetic acid (IAA), indole-3-acetaldehyde and Kyn can be produced by intestinal microorganisms through direct Trp transformation and also, partly, the kynurenine (Kyn) pathway. These metabolites play a critical role in maintaining the homeostasis of the gut and systematic immunity and also potentially affect the occurrence and development of diseases such as inflammatory bowel diseases, tumors, obesity and metabolic syndrome, diseases in the nervous system, infectious diseases, vascular inflammation and cardiovascular diseases and hepatic fibrosis. They can not only promote the differentiation and function of anti-inflammatory macrophages, Treg cells, CD4+CD8αα+ regulatory cells, IL-10+ and/or IL-35+B regulatory cells but also IL-22-producing innate lymphoid cells 3 (ILC3), which are involved in maintaining the gut mucosal homeostasis. These findings have important consequences in the immunotherapy against tumor and other immune-associated diseases. We will summarize here the recent advances in understanding the generation and regulation of tryptophan metabolites in the gut microbiota, the role of gut microbiota-derived tryptophan metabolites in different immune cells, the occurrence and development of diseases and immunotherapy against immune-associated diseases.

Background:Regulatory B cells (Bregs) are defective in many auto-immune diseases, i.e. rheumatoid arthritis (RA). The short-chain fatty acid (SCFA) acetate, derived mostly from gut microbial fermentation of dietary fiber, promotes anti-inflammatory regulatory T cells and protects mice from type 1 diabetes and colitis. We hypothesized that acetate could be a good candidate to promote Bregs in auto-immune diseases.Objectives:To assess the effect of acetate on Breg number and function,in vitroandin vivoin mice and humans.Methods:Bregs were defined as IL-10 producing regulatory B cells (B10 cells). Their number was assessed after overnight exposure to acetate (Ac 10 mM) and 4 hours of CpG, ionomycin and PMA in mice and after 24 hours of acetate +/- CpG and 4 hours of ionomycin and PMA in humans. Acetate was given to mice either intraperitoneally (twice at a 12-hour interval) or in drinking water for 3 weeks. Acetate-treated B cells were transferred to mice with collagen-antibody -induced arthritis to assess their function. To decipher the mechanisms behind the effect of acetate, we used inhibitors of GPR43 (CATPB), ATP synthase (oligomycin), glycolysis (2-DG), ACSS2 and ACLY and assessed protein lysine acetylation by flow cytometry on human B cells. Acetate and B10 cells were also assessed before and after a 7-day high-fibre diet in 12 healthy volunteers.Results:In mice, acetate promoted B10 cell differentiation bothin vitro(medians [IQR] 3.1 [0.4-3.7] and 9.9 [5.9-17.6]% of B for CpG and CpG+Ac respectively, p=0.002) andin vivowhen intraperitoneal injected(22 [14-29] and 31 [25-37]% of B for PBS and acetate respectively,p=0.03) or added to drinking water (17 [6-25] and 39 [26-40]% of B for water or acetate respectively, p=0.02). Adoptive transfer of acetate-treated B cells protected mice from arthritis compared to non-exposed B cells (ANOVA p=0.008). Acetate also promoted B10 cells from human blood cells (2.5 [1.6-2.7] and 3.4 [2.6-4.5] for unstimulated [Un] and Ac respectively, p=0.0001). Conversely to CpG, acetate specifically promoted IL-10, with no impact or a decrease of proinflammatory cytokines (IL-6: 17 [5-29]; 12 [3-21] and 40 [20-47]% B cells for Un, Ac and CpG respectively, p<0.01 for all comparisons and TNF-a: 48 [29-61]; 41 [28-67] and 69 [64-78]% B cells for Un, Ac and CpG respectively, p<0.01 for CpG vs Un or Ac, NS for acetate vs Un). Inhibition of GPR43 and ACLY did not impact acetate response, while inhibition of glycolysis significantly decreased its effect. Blockade of ACSS2, converting acetate into acetyl-CoA, decreased acetate-induced B10 cells. Acetate was associated with an increase of protein lysine acetylation which was not observed in presence of CpG alone, suggesting a different mechanism of action (2.0 [1.3-3.4]; 3.3 [2.4-5.4] and 1.4 [0.5-1.7]% B cells for Un, Ac and CpG respectively, p=0.002 for Un vs Ac, NS with CpG). Conversion of acetate into acetyl-CoA could thus be used for the acetylation of cytoplasmic protein, a post-translational modification that regulates key cellular processes, including energy metabolism. In addition, B10 cells had significantly more lysine-acetylated proteins than IL-10negB cells or TNF+B cells (5.3[3.9-7.3]; 3.2 [2.4-5.4] and 3.9 [2.7-6.2] % of B for B10, IL-10negB cells or TNF+B cells respectively, p<0.01 for all comparisons). Finally, dietary fiber supplementation in healthy individuals was associated with increased acetate and B10 cells in the blood, which were significantly correlated (R2=0.20, p=0.02).Conclusion:Our results suggest that acetate induces functional Bregs, through its conversion into acetyl-CoA, used for cell metabolism and protein acetylation. Delivery of acetate or acetate producing diets or bacteria might be a promising approach to restore Bregs in non-communicable diseases such as RA in which they are defective.Disclosure of Interests:Claire DAIEN Grant/research support from: from Pfizer, Abbvie, Roche-Chugaï, Novartis, Abivax, Sandoz, Consultant of: Abbvie, Abivax, BMS, MSD, Roche-Chugaï, Lilly, Novartis, Speakers bureau: Abbvie, Abivax, BMS, MSD, Roche-Chugaï, Lilly, Novartis, Jian Tan: None declared, Rachel Audo: None declared, Julie Mielle: None declared, Laurence Macia: None declared

Immunoglobulin A (IgA)–producing plasma cells derived from conventional B cells in the gut play an important role in maintaining the homeostasis of gut flora. Both T cell–dependent and T cell–independent IgA class switching occurs in the lymphoid structures in the gut, whose formation depends on lymphoid tissue inducers (LTis), a subset of innate lymphoid cells (ILCs). However, our knowledge on the functions of non-LTi helper-like ILCs, the innate counter parts of CD4 T helper cells, in promoting IgA production is still limited. By cell adoptive transfer and utilizing a unique mouse strain, we demonstrated that the generation of IgA-producing plasma cells from B cells in the gut occurred efficiently in the absence of both T cells and helper-like ILCs and without engaging TGF-β signaling. Nevertheless, B cell recruitment and/or retention in the gut required functional NKp46−CCR6+ LTis. Therefore, while CCR6+ LTis contribute to the accumulation of B cells in the gut through inducing lymphoid structure formation, helper-like ILCs are not essential for the T cell–independent generation of IgA-producing plasma cells.

Gut-associated lymphoid tissue (GALT), such as Peyer’s patches (PPs), are key inductive sites that generate IgA+ B cells, mainly through germinal center (GC) responses. The generation of IgA+ B cells is promoted by the presence of gut microbiota and dietary antigens. However, the function of GALT in the large intestine, such as cecal patches (CePs) and colonic patches (CoPs), and their regulatory mechanisms remain largely unknown. In this study, we demonstrate that the CePs possess more IgG2b+ B cells and have fewer IgA+ B cells than those in PPs from BALB/c mice with normal gut microbiota. Gene expression analysis of postswitched transcripts supported the differential expression of dominant antibody isotypes in B cells in GALT. Germ-free (GF) mice showed diminished GC B cells and had few IgA+ or IgG2b+ switched B cells in both the small and large intestinal GALT. In contrast, myeloid differentiation factor 88- (MyD88-) deficient mice exhibited decreased GC B cells and presented with reduced numbers of IgG2b+ B cells in CePs but not in PPs. Using ex vivo cell culture, we showed that CePs have a greater capacity to produce total and microbiota-reactive IgG2b, in addition to microbiota-reactive IgA, than the PPs. In line with the frequency of GC B cells and IgG2b+ B cells in CePs, there was a decrease in the levels of microbiota-reactive IgG2b and IgA in the serum of GF and MyD88-deficient mice. These data suggest that CePs have a different antibody production profile compared to PPs. Furthermore, the innate immune signals derived from gut microbiota are crucial for generating the IgG2b antibodies in CePs.

Although previous studies have implicated lymphocytes in the gut microvascular and inflammatory responses to ischemia-reperfusion (I/R), the lymphocyte population and lymphocyte-derived products that mediate these responses have not been defined. Platelet and leukocyte adhesion was measured in intestinal postcapillary venules of wild-type (WT) mice and mice genetically deficient in either CD4+ T cells (CD4−/−), CD8+ T cells (CD8−/−), B cells (B cell−/−), or interferon-γ (IFN-γ−/−) subjected to 45 min of ischemia and 4 h of reperfusion. The I/R-induced platelet and leukocyte recruitment responses were also evaluated following adoptive transfer of WT splenocytes into CD4−/−, CD8−/−, B cell−/−, and IFN-γ−/− mice. WT mice exposed to gut I/R exhibited significant increases in the adhesion of both platelets and leukocytes, compared with sham-WT mice. These blood cell adhesion responses to I/R were greatly attenuated in CD4−/−, CD8−/−, B cell−/−, and IFN-γ−/− mice. Adoptive transfer of WT splenocytes restored the WT responses to I/R in all mutants except the B cell−/− mice. These findings implicate both T and B cells and lymphocyte-derived IFN-γ as mediators of the proinflammatory and prothrombogenic phenotype assumed by intestinal microvessels after I/R.

Although morphologies are diverse, the common pattern in bilaterians is for passage of food in the gut to be controlled by nerves and endodermally derived neuron-like cells. In vertebrates, nitric oxide (NO) derived from enteric nerves controls relaxation of the pyloric sphincter. Here, we show that in the larvae of sea urchins, there are endoderm-derived neuronal nitric oxide synthase (nNOS)-positive cells expressing pan-neural marker, Synaptotagmin-B (SynB), in sphincters and that NO regulates the relaxation of the pyloric sphincter. Our results indicate that NO-dependent pylorus regulation is a shared feature within the deuterostomes, and we speculate that it was a characteristic of stem deuterostomes.

Abstract The IgMi mouse has normal B cell development; its B cells express an IgM B cell receptor but cannot class switch or secrete antibody. Thus, the IgMi mouse offers a model system by which to dissect out antibody-dependent and antibody-independent B cell function. Here, we provide the first detailed characterisation of the IgMi mouse post-Trichuris muris (T. muris) infection, describing expulsion phenotype, cytokine production, gut pathology and changes in T regulatory cells, T follicular helper cells and germinal centre B cells, in addition to RNA sequencing (RNA seq) analyses of wild-type littermates (WT) and mutant B cells prior to and post infection. IgMi mice were susceptible to a high-dose infection, with reduced Th2 cytokines and elevated B cell-derived IL-10 in mesenteric lymph nodes (MLN) compared to controls. A low-dose infection regime revealed IgMi mice to have significantly more apoptotic cells in the gut compared to WT mice, but no change in intestinal inflammation. IL-10 levels were again elevated. Collectively, this study showcases the potential of the IgMi mouse as a tool for understanding B cell biology and suggests that the B cell plays both antibody-dependent and antibody-independent roles post high- and low-dose T. muris infection. Key messages During a high-dose T. muris infection, B cells are important in maintaining the Th1/Th2 balance in the MLN through an antibody-independent mechanism. High levels of IL-10 in the MLN early post-infection, and the presence of IL-10-producing B cells, correlates with susceptibility to T. muris infection. B cells maintain gut homeostasis during chronic T. muris infection via an antibody-dependent mechanism.

AbstractA mounting body of evidence indicates that dietary fiber (DF) metabolites produced by commensal bacteria play essential roles in balancing the immune system. DF, considered nonessential nutrients in the past, is now considered to be necessary to maintain adequate levels of immunity and suppress inflammatory and allergic responses. Short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, are the major DF metabolites and mostly produced by specialized commensal bacteria that are capable of breaking down DF into simpler saccharides and further metabolizing the saccharides into SCFAs. SCFAs act on many cell types to regulate a number of important biological processes, including host metabolism, intestinal functions, and immunity system. This review specifically highlights the regulatory functions of DF and SCFAs in the immune system with a focus on major innate and adaptive lymphocytes. Current information regarding how SCFAs regulate innate lymphoid cells, T helper cells, cytotoxic T cells, and B cells and how these functions impact immunity, inflammation, and allergic responses are discussed.

Abstract Although human B cells have been extensively studied, most reports have used peripheral blood as a source. Here, we used a unique tissue resource derived from healthy organ donors to deeply characterize human B-cell compartments across multiple tissues and donors. These datasets revealed that B cells in the blood are not in homeostasis with compartments in other tissues. We found striking donor-to-donor variability in the frequencies and isotype of CD27+ memory B cells (MBCs). A comprehensive antibody-based screen revealed markers of MBC and allowed identification of novel MBC subsets with distinct functions defined according to surface expression of CD69 and CD45RB. We defined a tissue-resident MBC phenotype that was predominant in the gut but absent in blood. RNA-sequencing of MBC subsets from multiple tissues revealed a tissue-resident MBC gene signature as well as gut- and spleen-specific signatures. Overall, these studies provide novel insights into the nature and function of human B-cell compartments across multiple tissues.