An efficient B cell immunity requires a dynamic equilibrium between positive and negative signals. In germinal centers (GCs), T follicular helper cells are supposed to be the positive regulator while ...T follicular regulatory (Tfr) cells were assigned to be the negative regulators. Indeed, Tfr cells are considered as a homogenous cell population dedicated to dampen the GC extent. Moreover, Tfr cells prevent autoimmunity since their dysregulation leads to production of self-reactive antibodies (Ab). However, a growing corpus of evidence has revealed additional and unexpected functions for Tfr cells in the regulation of B cell responses. This review provides an overview of the Tfr cell contribution and presents Tfr cell proprieties in the context of vaccination.
T follicular regulatory (Tfr) cells are a subset of Foxp3(+) regulatory T (Treg) cells that form in response to immunization or infection, which localize to the germinal centre where they control the ...magnitude of the response. Despite an increased interest in the role of Tfr cells in humoral immunity, many fundamental aspects of their biology remain unknown, including whether they recognize self- or foreign antigen. Here we show that Tfr cells can be specific for the immunizing antigen, irrespective of whether it is a self- or foreign antigen. We show that, in addition to developing from thymic derived Treg cells, Tfr cells can also arise from Foxp3(-) precursors in a PD-L1-dependent manner, if the adjuvant used is one that supports T-cell plasticity. These findings have important implications for Tfr cell biology and for improving vaccine efficacy by formulating vaccines that modify the Tfr:Tfh cell ratio.
Follicular helper T cells regulate high-affinity antibody production. Memory follicular helper T cells can be local in draining lymphoid organs and circulate in the blood, but the underlying ...mechanisms of this subdivision are unresolved. Here we show that both memory follicular helper T subsets sustain B-cell responses after reactivation. Local cells promote more plasma cell differentiation, whereas circulating cells promote more secondary germinal centers. In parallel, local memory B cells are homogeneous and programmed to become plasma cells, whereas circulating memory B cells are able to rediversify. Local memory follicular helper T cells have higher affinity T-cell receptors, which correlates with expression of peptide MHC-II at the surface of local memory B cells only. Blocking T-cell receptor-peptide MHC-II interactions induces the release of local memory follicular helper T cells in the circulating compartment. Our studies show that memory follicular helper T localization is highly intertwined with memory B cells, a finding that has important implications for vaccine design.Tfh cells can differentiate into memory cells. Here the authors describe distinct functional and phenotypic profiles of these memory Tfh cells dependent on their anatomical localization to the lymphoid organs or to the circulation.
Maturation of B cells in Germinal Centers (GC) is a hallmark in adaptive immunity and the basis of successful vaccines that protect us against lethal infections. Nonetheless, vaccination efficacy is ...very much reduced in aged population and against highly mutagenic viruses. Therefore, it is key to understand how B cell selection takes place in GC in order to develop new and fully protective vaccines. The cellular mechanisms that control selection of GC B cells are performed by different T cell populations. On one side, cognate entanglement of B cells with T follicular helper (Tfh) cells through cytokines and co-stimulatory signals promotes survival, proliferation, mutagenesis and terminal differentiation of GC B cells. On the other hand, regulatory T cells have also been reported within GC and interfere with T cell help for antibody production. These cells have been classified as a distinct T cell sub-population called T Follicular regulatory cells (Tfr). In this review, we investigate the phenotype, function and differentiation of these two cell populations. In addition, based on the different functions of these cell subsets, we highlight the open questions surrounding their heterogeneity.
•CD8+Foxp3+ T cells are the counterpart to the better studies CD4+Foxp3+ Treg population.•CD8+Foxp3+ T cells share a common transcriptional profile and suppressive function with CD4+Foxp3+ ...Tregs.•CD8+Foxp3+ T cells have been reported to have a role in several disease states.•CD8+Foxp3+ T cells may have a unique function in regulating B cell responses.
CD4+Foxp3+ Regulatory T cells (Tregs) are essential for maintaining self-tolerance and are increasingly recognised to have important roles in tissue homeostasis and repair. In the CD8 compartment an analogous Foxp3+ population is present, which shares phenotypic aspects with the more common CD4+Foxp3+Treg population. While oft neglected for their low frequency, there is increasing evidence that these CD8+Foxp3+ cells are bona fide regulatory cells, with both shared and distinct characteristics from their CD4+ analogue. Here we focus on the evidence for a regulatory function of CD8+Foxp3+ cells, and the potential unique role this neglected lineage may play in immune homeostasis and disease prevention.
Characterization and counting of the different immune cell subpopulations are largely used in order to predict the quality of vaccination or the progression of diseases. As such, flow cytometry is a ...valuable technology to perform an exact cartography of the immune cell subsets. In the context of B-cell responses, specialized structures emerge in B-follicles of second lymphoid organs where B-cells "undergo maturation processes under the guidance of specific T-cells, follicular helper T-cells, and follicular regulatory T-cells. Thus, tracking these cell types is of high interest, especially in the context of protein vaccination. In this purpose, we describe here, how we can track antigen-specific follicular helper T-cells and follicular regulatory T-cells by flow cytometry after protein vaccination in nonmodified wild-type mice, which ultimately provides a comprehensive way to better understand the function of these particular cells in vivo.
Acute pyelonephritis (APN), which is mainly caused by uropathogenic Escherichia coli (UPEC), is the most common bacterial complication in renal transplant recipients receiving immunosuppressive ...treatment. However, it remains unclear how immunosuppressive drugs, such as the calcineurin inhibitor cyclosporine A (CsA), decrease renal resistance to UPEC. Here, we investigated the effects of CsA in host defense against UPEC in an experimental model of APN. We show that CsA-treated mice exhibit impaired production of the chemoattractant chemokines CXCL2 and CXCL1, decreased intrarenal recruitment of neutrophils, and greater susceptibility to UPEC than vehicle-treated mice. Strikingly, renal expression of Toll-like receptor 4 (Tlr4) and nucleotide-binding oligomerization domain 1 (Nod1), neutrophil migration capacity, and phagocytic killing of E. coli were significantly reduced in CsA-treated mice. CsA inhibited lipopolysaccharide (LPS)-induced, Tlr4-mediated production of CXCL2 by epithelial collecting duct cells. In addition, CsA markedly inhibited Nod1 expression in neutrophils, macrophages, and renal dendritic cells. CsA, acting through inhibition of the nuclear factor of activated T-cells (NFATs), also markedly downregulated Nod1 in neutrophils and macrophages. Silencing the NFATc1 isoform mRNA, similar to CsA, downregulated Nod1 expression in macrophages, and administration of the 11R-VIVIT peptide inhibitor of NFATs to mice also reduced neutrophil bacterial phagocytosis and renal resistance to UPEC. Conversely, synthetic Nod1 stimulating agonists given to CsA-treated mice significantly increased renal resistance to UPEC. Renal transplant recipients receiving CsA exhibited similar decrease in NOD1 expression and neutrophil phagocytosis of E. coli. The findings suggest that such mechanism of NFATc1-dependent inhibition of Nod1-mediated innate immune response together with the decrease in Tlr4-mediated production of chemoattractant chemokines caused by CsA may contribute to sensitizing kidney grafts to APN.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Opioid-dependent immune-mediated analgesic effects have been broadly reported upon inflammation. In preclinical mouse models of intestinal inflammatory diseases, the local release of enkephalins ...(endogenous opioids) by colitogenic T lymphocytes alleviate inflammation-induced pain by down-modulating gut-innervating nociceptor activation in periphery. In this study, we wondered whether this immune cell-derived enkephalin-mediated regulation of the nociceptor activity also operates under steady state conditions. Here, we show that chimeric mice engrafted with enkephalin-deficient bone marrow cells exhibit not only visceral hypersensitivity but also an increase in both epithelial paracellular and transcellular permeability, an alteration of the microbial topography resulting in increased bacteria-epithelium interactions and a higher frequency of IgA-producing plasma cells in Peyer's patches. All these alterations of the intestinal homeostasis are associated with an anxiety-like behavior despite the absence of an overt inflammation as observed in patients with irritable bowel syndrome. Thus, our results show that immune cell-derived enkephalins play a pivotal role in maintaining gut homeostasis and normal behavior in mice. Because a defect in the mucosal opioid system remarkably mimics some major clinical symptoms of the irritable bowel syndrome, its identification might help to stratify subgroups of patients.
In order to ascertain the significance of transmembrane tumor necrosis factor (tmTNF) reverse signaling in vivo, we generated a triple transgenic mouse model (3TG, TNFR1−/−, TNFR2−/−, and tmTNFKI/KI) ...in which all canonical tumor necrosis factor (TNF) signaling was abolished. In bone-marrow-derived macrophages harvested from these mice, various anti-TNF biologics induced the expression of genes characteristic of alternative macrophages and also inhibited the expression of pro-inflammatory cytokines mainly through the upregulation of arginase-1. Injections of TNF inhibitors during arthritis increased pro-resolutive markers in bone marrow precursors and joint cells leading to a decrease in arthritis score. These results demonstrate that the binding of anti-TNF biologics to tmTNF results in decreased arthritis severity. Collectively, our data provide evidence for the significance of tmTNF reverse signaling in the modulation of arthritis. They suggest a complementary interpretation of anti-TNF biologics effects in the treatment of inflammatory diseases and pave the way to studies focused on new arginase-1-dependent therapeutic targets.
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•In vivo demonstration of tmTNF reverses signaling existence•tmTNF reverse signaling induces anti-oxidative stress response•tmTNF reverse signaling induces an arginase-1-mediated anti-inflammatory response•Reverse signaling is a complementary mechanism to TNF neutralization by anti-TNF
Immunology; Cell Biology
A high-fat diet (HFD) induces metabolic disease and low-grade metabolic inflammation in response to changes in the intestinal microbiota through as-yet-unknown mechanisms. Here, we show that a ...HFD-derived ileum microbiota is responsible for a decrease in Th17 cells of the lamina propria in axenic colonized mice. The HFD also changed the expression profiles of intestinal antigen-presenting cells and their ability to generate Th17 cells in vitro. Consistent with these data, the metabolic phenotype was mimicked in RORγt-deficient mice, which lack IL17 and IL22 function, and in the adoptive transfer experiment of T cells from RORγt-deficient mice into Rag1-deficient mice. We conclude that the microbiota of the ileum regulates Th17 cell homeostasis in the small intestine and determines the outcome of metabolic disease.
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•HFD-induced T2D decreases the number of ileum IL17/RORγt CD4 T cells•IL17/RORγt-deficient CD4 T cells induce T2D and obesity•HFD-induced ileum microbiota dysbiosis lowers intestinal IL17/RORγt-CD4 T cells•HFD reduces antigen presenting cell ability to induce Th17 cell differentiation
Obesity and type 2 diabetes have been linked to the gut microbiota. Garidou et al. show that a high-fat diet induces gut microbiota dysbiosis which impairs the intestinal immune defense, including reduced intestinal IL 17 T cells. The intestinal immunity changes precede the onset of diabetes.
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