Antibodies to DNA and chromatin drive autoimmunity in systemic lupus erythematosus (SLE). Null mutations and hypomorphic variants of the secreted deoxyribonuclease DNASE1L3 are linked to familial and ...sporadic SLE, respectively. We report that DNASE1L3-deficient mice rapidly develop autoantibodies to DNA and chromatin, followed by an SLE-like disease. Circulating DNASE1L3 is produced by dendritic cells and macrophages, and its levels inversely correlate with anti-DNA antibody response. DNASE1L3 is uniquely capable of digesting chromatin in microparticles released from apoptotic cells. Accordingly, DNASE1L3-deficient mice and human patients have elevated DNA levels in plasma, particularly in circulating microparticles. Murine and human autoantibody clones and serum antibodies from human SLE patients bind to DNASE1L3-sensitive chromatin on the surface of microparticles. Thus, extracellular microparticle-associated chromatin is a potential self-antigen normally digested by circulating DNASE1L3. The loss of this tolerance mechanism can contribute to SLE, and its restoration may represent a therapeutic opportunity in the disease.
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•Rapid anti-DNA antibody response, followed by SLE in Dnase1l3-deficient mice•Autoreactivity is repressed by circulating DNASE1L3 and is independent of STING•DNASE1L3 digests genomic DNA in microparticles released from apoptotic cells•DNASE1L3 prevents autoantibody binding to chromatin on microparticle surface
Extracellular microparticle-associated chromatin is a potential self-antigen normally digested by circulating DNASE1L3. The loss of this tolerance mechanism in mice and humans contributes to lupus, and the restoration of this mechanism may represent a therapeutic opportunity in the disease.
Commensal bacteria are necessary for the development and maintenance of a healthy immune system. Harnessing the ability of microbiota to affect host immunity is considered an important therapeutic ...strategy for many mucosal and nonmucosal immune-related conditions, such as inflammatory bowel diseases (IBDs), celiac disease, metabolic syndrome, diabetes, and microbial infections. In addition to well-established immunostimulatory effects of the microbiota, the presence of individual mutualistic commensal bacteria with immunomodulatory effects has been described. These organisms are permanent members of the commensal microbiota and affect host immune homeostasis in specific ways. Identification of individual examples of such immunomodulatory commensals and understanding their mechanisms of interaction with the host will be invaluable in designing therapeutic strategies to reverse intestinal dysbiosis and recover immunological homeostasis.
Intestinal Th17 cells are induced and accumulate in response to colonization with a subgroup of intestinal microbes such as segmented filamentous bacteria (SFB) and certain extracellular pathogens. ...Here, we show that adhesion of microbes to intestinal epithelial cells (ECs) is a critical cue for Th17 induction. Upon monocolonization of germ-free mice or rats with SFB indigenous to mice (M-SFB) or rats (R-SFB), M-SFB and R-SFB showed host-specific adhesion to small intestinal ECs, accompanied by host-specific induction of Th17 cells. Citrobacter rodentium and Escherichia coli O157 triggered similar Th17 responses, whereas adhesion-defective mutants of these microbes failed to do so. Moreover, a mixture of 20 bacterial strains, which were selected and isolated from fecal samples of a patient with ulcerative colitis on the basis of their ability to cause a robust induction of Th17 cells in the mouse colon, also exhibited EC-adhesive characteristics.
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•A strong correlation between epithelial adhesion and Th17 induction by SFB and EHEC•Twenty Th17-inducing strains isolated from human feces show epithelial-adhesive property•Bacterial adhesion elicits a Th17-inducing gene-expression program in epithelium
The adhesion of specific members of the gut microbiome to intestinal epithelial cells is found to be essential for the induction of Th17 cells, thus highlighting location as an additional layer of regulation for the adaptive immune system.
How commensal microbiota contributes to immune cell homeostasis at barrier surfaces is poorly understood. Lamina propria (LP) T helper 17 (Th17) cells participate in mucosal protection and are ...induced by commensal segmented filamentous bacteria (SFB). Here we show that MHCII-dependent antigen presentation of SFB antigens by intestinal dendritic cells (DCs) is crucial for Th17 cell induction. Expression of MHCII on CD11c+ cells was necessary and sufficient for SFB-induced Th17 cell differentiation. Most SFB-induced Th17 cells recognized SFB in an MHCII-dependent manner. SFB primed and induced Th17 cells locally in the LP and Th17 cell induction occurred normally in mice lacking secondary lymphoid organs. The importance of other innate cells was unveiled by the finding that MHCII deficiency in group 3 innate lymphoid cells (ILCs) resulted in an increase in SFB-independent Th17 cell differentiation. Our results outline the complex role of DCs and ILCs in the regulation of intestinal Th17 cell homeostasis.
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•Presentation of SFB antigens by iDC is required for Th17 cell induction by SFB•SFB-induced Th17 cells recognize SFB antigens•SFB prime CD4 T cells and induce Th17 cell differentiation in the gut mucosa•Loss of MHCII on RORγt ILC leads to Th17 cell differentiation in the absence of SFB
Dendritic cells (DCs) in tissues and lymphoid organs comprise distinct functional subsets that differentiate in situ from circulating progenitors. Tissue-specific signals that regulate DC subset ...differentiation are poorly understood. We report that DC-specific deletion of the Notch2 receptor caused a reduction of DC populations in the spleen. Within the splenic CD11b
+ DC subset, Notch signaling blockade ablated a distinct population marked by high expression of the adhesion molecule Esam. The Notch-dependent Esam
hi DC subset required lymphotoxin beta receptor signaling, proliferated in situ, and facilitated CD4
+ T cell priming. The Notch-independent Esam
lo DCs expressed monocyte-related genes and showed superior cytokine responses. In addition, Notch2 deletion led to the loss of CD11b
+CD103
+ DCs in the intestinal lamina propria and to a corresponding decrease of IL-17-producing CD4
+ T cells in the intestine. Thus, Notch2 is a common differentiation signal for T cell-priming CD11b
+ DC subsets in the spleen and intestine.
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► Notch2 controls differentiation of splenic classical DCs ► Notch2 dependence defines a distinct Esam
hi population of splenic CD11b
+ DCs ► The Esam
hi CD11b
+ DCs are required for CD4
+ T cell priming in the spleen ► Notch2 controls differentiation of CD11b
+CD103
+ DCs in the intestinal lamina propria
T Cell Responses to the Microbiota Ivanov, Ivaylo I; Tuganbaev, Timur; Skelly, Ashwin N ...
Annual review of immunology,
04/2022, Letnik:
40, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The immune system employs recognition tools to communicate with its microbial evolutionary partner. Among all the methods of microbial perception, T cells enable the widest spectrum of microbial ...recognition resolution, ranging from the crudest detection of whole groups of microbes to the finest detection of specific antigens. The application of this recognition capability to the crucial task of combatting infections has been the focus of classical immunology. We now appreciate that the coevolution of the immune system and the microbiota has led to development of a lush immunological decision tree downstream of microbial recognition, of which an inflammatory response is but one branch. In this review we discuss known T cell-microbe interactions in the gut and place them in the context of an algorithmic framework of recognition, context-dependent interpretation, and response circuits across multiple levels of microbial recognition resolution. The malleability of T cells in response to the microbiota presents an opportunity to edit immune response cellularity, identity, and functionality by utilizing microbiota-controlled pathways to promote human health.
How intestinal microbes regulate metabolic syndrome is incompletely understood. We show that intestinal microbiota protects against development of obesity, metabolic syndrome, and pre-diabetic ...phenotypes by inducing commensal-specific Th17 cells. High-fat, high-sugar diet promoted metabolic disease by depleting Th17-inducing microbes, and recovery of commensal Th17 cells restored protection. Microbiota-induced Th17 cells afforded protection by regulating lipid absorption across intestinal epithelium in an IL-17-dependent manner. Diet-induced loss of protective Th17 cells was mediated by the presence of sugar. Eliminating sugar from high-fat diets protected mice from obesity and metabolic syndrome in a manner dependent on commensal-specific Th17 cells. Sugar and ILC3 promoted outgrowth of Faecalibaculum rodentium that displaced Th17-inducing microbiota. These results define dietary and microbiota factors posing risk for metabolic syndrome. They also define a microbiota-dependent mechanism for immuno-pathogenicity of dietary sugar and highlight an elaborate interaction between diet, microbiota, and intestinal immunity in regulation of metabolic disorders.
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•Commensal-induced Th17 cells regulate epithelial lipid absorption•Sugar and ILC3 increase Faecalibaculum rodentium to displace Th17-inducing bacteria•Microbiota-induced Th17 cells protect from diet-induced obesity and metabolic disease•Sugar eliminates commensal Th17 cells to increase the risk for metabolic disease
Sugar in mouse diets promotes metabolic disease by upsetting the gut microbial balance and driving loss of the Th17 cells that regulate lipid absorption by the intestinal epithelium.
Commensal bacteria regulate the homeostasis of host effector immune cell subsets. The mechanisms involved in this commensal–host crosstalk are not well understood. Intestinal epithelial cells (IECs) ...not only create a physical barrier between the commensals and immune cells in host tissues, but also facilitate interactions between them. Perturbations of epithelial homeostasis or function lead to the development of intestinal disorders such as inflammatory bowel diseases (IBD) and intestinal cancer. IECs receive signals from commensals and produce effector immune molecules. IECs also affect the function of immune cells in the lamina propria. Here we discuss some of these properties of IECs that define them as innate immune cells. We focus on how IECs may integrate and transmit signals from individual commensal bacteria to mucosal innate and adaptive immune cells for the establishment of the unique mucosal immunological equilibrium.
The March 2013 issue of Immunology and Cell Biology contains a special feature that focuses on the role of the intestinal epithelial barrier and innate immune cells, examines their crosstalk with the commensal flora, and assesses their contribution to intestinal immunity in health and disease. There is a complexity of interaction among these distinct components and the Reviews of this special feature examine, unravel and investigate the action and reaction in the intestinal homeostasis‐perturbation cycle. Further background information on this important topic is available through the accompanying web focus which links to related articles from across Nature Publishing Group.
Commensal microbes can have a substantial impact on autoimmune disorders, but the underlying molecular and cellular mechanisms remain largely unexplored. We report that autoimmune arthritis was ...strongly attenuated in the K/BxN mouse model under germ-free (GF) conditions, accompanied by reductions in serum autoantibody titers, splenic autoantibody-secreting cells, germinal centers, and the splenic T helper 17 (Th17) cell population. Neutralization of interleukin-17 prevented arthritis development in specific-pathogen-free K/BxN mice resulting from a direct effect of this cytokine on B cells to inhibit germinal center formation. The systemic deficiencies of the GF animals reflected a loss of Th17 cells from the small intestinal lamina propria. Introduction of a single gut-residing species, segmented filamentous bacteria, into GF animals reinstated the lamina propria Th17 cell compartment and production of autoantibodies, and arthritis rapidly ensued. Thus, a single commensal microbe, via its ability to promote a specific Th cell subset, can drive an autoimmune disease.
► Commensal microbes drive arthritis development in the K/BxN mouse model ► Germ-free mice had deficits in gut and spleen Th17 cells and in serum autoantibodies ► IL-17 blockade could prevent arthritis through a direct effect on splenic B cells ► Segmented filamentous bacteria could alone trigger arthritis in germ-free K/BxN mice
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