A regulatory TRIF/IL-1R1 axis controls T-dependent IgA production in the intestines
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE328882 | GEO | 2026/06/01
REPOSITORIES: GEO
Similar Datasets
Project description:We report here unrelated HSE patients with autosomal recessive (AR) or autosomal dominant (AD) TRIF deficiency. The AR form of the disease is due to a homozygous nonsense mutation, resulting in a complete absence of the TRIF protein. Both the TLR3 and the TRIF-dependent TLR4 signaling pathways are abolished. The AD form of TRIF deficiency is due to a heterozygous missense mutation resulting in a dysfunctional protein. The TLR3 signaling pathway is impaired, whereas the TRIF-dependent TLR4 pathway is unaffected. Both patients however showed reduced capacity to respond to cytosolic double stranded RNA, consistent with recent reports of TRIF’s involvement in the DExD/H-box helicases pathway.
2011-10-20 | GSE32390 | GEO
Project description:We report here unrelated HSE patients with autosomal recessive (AR) or autosomal dominant (AD) TRIF deficiency. The AR form of the disease is due to a homozygous nonsense mutation, resulting in a complete absence of the TRIF protein. Both the TLR3 and the TRIF-dependent TLR4 signaling pathways are abolished. The AD form of TRIF deficiency is due to a heterozygous missense mutation resulting in a dysfunctional protein. The TLR3 signaling pathway is impaired, whereas the TRIF-dependent TLR4 pathway is unaffected. Both patients however showed reduced capacity to respond to cytosolic double stranded RNA, consistent with recent reports of TRIF’s involvement in the DExD/H-box helicases pathway. Skin fibroblast cell lines were derived from healthy controls (n=3), patient with deficiencies for TRIF (n=1), MYD88 (n=1), and TLR3 (n=1) and cultured for 4 hours in the presence of IL1B (20ng/ml) or poly I:C (25ng/ml) or left unstimulated for the same length of time. PBMCs (previously frozen) collected from a healthy control (n=1) and patients with deficiencies for TRIF (n=1), and MYD88 (n=1) were cultured together with LPS (10ng/ml) or R848 (3ug/ml) for 2hrs or left unstimulated for the same length of time.
2011-10-19 | E-GEOD-32390 | biostudies-arrayexpress
Project description:Necroptosis is a lytic form of cell death that is mediated by the kinase RIPK3 and the pseudokinase MLKL when caspase-8 is inhibited downstream of death receptors, toll-like receptor 3 (TLR3), TLR4, and the intracellular Z-form nucleic acid sensor ZBP1. Oligomerization and activation of RIPK3 is driven by interactions with the kinase RIPK1, the TLR adaptor TRIF, or ZBP1. In this study, we use immunohistochemistry (IHC) and in situ hybridization (ISH) assays to generate a tissue atlas characterizing RIPK1, RIPK3, Mlkl, and ZBP1 expression in mouse tissues. RIPK1, RIPK3, and Mlkl were co-expressed in most immune cell populations, endothelial cells, and many mucosal epithelia. ZBP1 was expressed in many immune populations, but had more variable expression in epithelia compared to RIPK1, RIPK3, and Mlkl. Intriguingly, expression of ZBP1 was elevated in Casp8-/- Tnfr1-/- embryos prior to their succumbing to aberrant necroptosis around embryonic day 15. ZBP1 contributed to this embryonic lethality because rare Casp8-/- Tnfr1-/- Zbp1-/- mice survived until after birth. Necroptosis mediated by TRIF contributed to the demise of Casp8-/- Tnfr1-/- Zbp1-/- pups in the perinatal period. Of note, Casp8-/- Tnfr1-/- Trif-/- Zbp1-/- mice exhibited autoinflammation and morbidity, typically within 5-7 weeks of being born, which is not seen in Casp8-/- Ripk1-/- Trif-/- Zbp1-/-, Casp8-/- Ripk3-/-, or Casp8-/- Mlkl-/- mice. Therefore, after birth, loss of caspase-8 probably unleashes RIPK1-dependent necroptosis driven by death receptors other than TNFR1.
2024-04-01 | GSE254754 | GEO
Project description:Redundant mechanisms support IgA responses to intestinal antigens. These include multiple priming sites (mesenteric lymph nodes (MLN), Peyer's patches and isolated lymphoid follicles) and various cytokines that promote class switch to IgA, even in the absence of T cells. In spite of these back-up mechanisms, vaccination against enteric pathogens such as Rotavirus has limited success in some populations.Genetic and environmental signals experienced during early life are known to influence mucosal immunity, yet the mechanisms for how these exposures operate remain unclear. Here we used Rotavirus infection to follow antigen-specific IgA responses through time and in different gut compartments. Using genetic and pharmacological approaches, we tested the role of a pathway known to support IgA responses (Lymphotoxin - LT) at different developmental stages. We found that LT-beta receptor (LTβR) signalling in early life programs intestinal IgA responses in adulthood by affecting antibody class switch recombination to IgA and subsequent generation of IgA antibody-secreting cells within an intact MLN. In addition, early life LTβR signalling dictates the phenotype and function of MLN stromal cells in order to support IgA responses in the adult. Collectively, our studies uncover new mechanistic insights into how early life LTβR signalling impacts mucosal immune responses during adulthood.
2019-10-05 | GSE138456 | GEO
Project description:Redundant mechanisms support IgA responses to intestinal antigens. These include multiple priming sites (mesenteric lymph nodes (MLN), Peyer's patches and isolated lymphoid follicles) and various cytokines that promote class switch to IgA, even in the absence of T cells. In spite of these back-up mechanisms, vaccination against enteric pathogens such as Rotavirus has limited success in some populations.Genetic and environmental signals experienced during early life are known to influence mucosal immunity, yet the mechanisms for how these exposures operate remain unclear. Here we used Rotavirus infection to follow antigen-specific IgA responses through time and in different gut compartments. Using genetic and pharmacological approaches, we tested the role of a pathway known to support IgA responses (Lymphotoxin - LT) at different developmental stages. We found that LT-beta receptor (LTβR) signalling in early life programs intestinal IgA responses in adulthood by affecting antibody class switch recombination to IgA and subsequent generation of IgA antibody-secreting cells within an intact MLN. In addition, early life LTβR signalling dictates the phenotype and function of MLN stromal cells in order to support IgA responses in the adult. Collectively, our studies uncover new mechanistic insights into how early life LTβR signalling impacts mucosal immune responses during adulthood.
2019-10-05 | GSE138455 | GEO
Project description:Mucosal immunization and mucosal IgA offer significant promise in protecting against airborne pathogens, including SARS-CoV-2. However, the conditions and mechanisms that lead to the robust induction of mucosal IgA responses following mucosal vaccination remain poorly understood. It is also currently debatable whether mucosal vaccination is still warranted given that most individuals in developed countries have established a hybrid immunity from vaccination and infection. Here we characterized respiratory mucosal immune responses after SARS-CoV-2 infection, vaccination or both in humans. We found that hybrid immunity resulted in moderately increased mucosal IgA and neutralizing antibody responses compared to infection or vaccination alone. However, a direct comparison of hybrid immunity and a mucosal adenovirus-based booster vaccination in animal models revealed that respiratory booster immunization elicited markedly stronger and more durable mucosal IgA, T cell response, and protective immunity against SARS-CoV-2, supporting the promise of respiratory mucosal vaccination. Mechanistically, we found that mucosal booster immunization induced local IgA-secreting cells in the respiratory mucosa, aided by pulmonary CD4+ T cells in situ. Strikingly, local IL-21-producing Blimp-1+ Th1 effector cells were critical in mediating the CD4+ T cell help for IgA production. Furthermore, lung macrophages were important for this mucosal IgA response via the production of TGF-β. Consequently, Spike mRNA coated with pulmonary surfactant (PS) containing liposomes, rationally designed to target lung macrophages, elicits a stronger mucosal IgA response. Collectively, our results uncover a local cellular network supporting enhanced mucosal IgA responses, with implications for the development of optimal mucosal immunization strategies against SARS-CoV-2 and other respiratory pathogens.
2025-11-13 | GSE298731 | GEO
Project description:Mucosal immunization and mucosal IgA offer significant promise in protecting against airborne pathogens, including SARS-CoV-2. However, the conditions and mechanisms that lead to the robust induction of mucosal IgA responses following mucosal vaccination remain poorly understood. It is also currently debatable whether mucosal vaccination is still warranted given that most individuals in developed countries have established a hybrid immunity from vaccination and infection. Here we characterized respiratory mucosal immune responses after SARS-CoV-2 infection, vaccination or both in humans. We found that hybrid immunity resulted in moderately increased mucosal IgA and neutralizing antibody responses compared to infection or vaccination alone. However, a direct comparison of hybrid immunity and a mucosal adenovirus-based booster vaccination in animal models revealed that respiratory booster immunization elicited markedly stronger and more durable mucosal IgA, T cell response, and protective immunity against SARS-CoV-2, supporting the promise of respiratory mucosal vaccination. Mechanistically, we found that mucosal booster immunization induced local IgA-secreting cells in the respiratory mucosa, aided by pulmonary CD4+ T cells in situ. Strikingly, local IL-21-producing Blimp-1+ Th1 effector cells were critical in mediating the CD4+ T cell help for IgA production. Furthermore, lung macrophages were important for this mucosal IgA response via the production of TGF-β. Consequently, Spike mRNA coated with pulmonary surfactant (PS) containing liposomes, rationally designed to target lung macrophages, elicits a stronger mucosal IgA response. Collectively, our results uncover a local cellular network supporting enhanced mucosal IgA responses, with implications for the development of optimal mucosal immunization strategies against SARS-CoV-2 and other respiratory pathogens.
2025-11-13 | GSE297825 | GEO
Project description:Several human lymphocyte subsets express the novel secretory IgA receptor FCRL3. Secretory IgA binding to FCRL3 mAb diminishes the inhibitory capacity of regulatory T cells and promotes a Th17-like phenotype. Here we report that in CD4+ regulatory T cells and CD8+ terminal effector T cells secretory IgA induced a shared inflammatory gene signature that included PTGS2 encoding COX2, and the prototypic inflammatory cytokine genes IL1A, IL1B, and IL8. Secretory IgA in regulatory T cells also elevated gene transcripts required for lineage identity and function. Secretory IgA promoted IL-1β, IL-6, IL-8, IL-10, IFN-γ, and TNF-α protein secretion by both T cell types. . We propose that secretory IgA provokes in regulatory and effector T cells a coordinated inflammatory response to facilitate mucosal pathogen clearance.
2025-04-07 | GSE277028 | GEO
Project description:Immunoglobulin A (IgA) most predominant antibody isotype at mucosal surfaces and is regulated by both T cell-dependent (TD) and independent (TI) mechanisms. In the TD pathway, T follicular helper (TFH) cells provide help to B cells to generate high-affinity antibodies. T follicular regulatory (TFR) cells fine-tune antibody responses, but precisely how these cellsregulate microbiota-directed IgA at mucosal sites has been unclear. Here, we used a TFR-deficient mouse model (Foxp3Cre Bcl6fl/fl; Bcl6FC) in which the gut microbiota develops in the absence of TFR cells, while the broader regulatory T cell compartment remains intact. While Bcl6FC mice showed similar levels of IgA-coated commensal bacteria to wild-type mice in the naïve state, following oral immunization, Bcl6FC mice exhibited a durable increase in IgA-coated commensal bacteria in feces and small intestine, without changes in overall community composition or epithelial barrier permeability. IgA-seq analysis of Bcl6FC mice revealed an increased diversity of IgA-coated taxa, both in naïve and orally immunized mice. IgA coating index analysis, a measure of IgA affinity, identified higher IgA binding to multiple taxa in Bcl6C mice compared to control mice. Consistent with these findings, sera from immunized Bcl6FC mice showed increased IgA binding to Alloprevotella and Klebsiella species but not to E. coli or Group A/B Streptococcus compared to control mice. B cell receptor repertoire sequencing demonstrated divergent patterns of somatic hypermutation (SMH) for IgA and IgG, where TFR cells repressed IgA SMH but enhanced IgG somatic hypermutation. Mechanistically, suppression of commensal-directed IgA required TFR-derived IL-10 but was independent of CTLA-4. IL-10 directly inhibited TGF-β-driven IgA class switching of B cells in vitro. Together, our data identify TFR cells as critical gatekeepers of mucosal IgA responses, constraining commensal-specific IgA responses through a novel IL-10-dependent pathway. Our findings haveimportant implications for regulation of the microbiome by TFR cells and IgA.
2026-04-15 | GSE320270 | GEO
Project description:Lipopolysaccharide (LPS), a Toll-like receptor (TLR) 4 ligand, activates intracellular signaling via adaptors, MyD88 and TRIF, leading to the expression of various genes including proinflammatory cytokines. We used microarrays to examine influence of MyD88 or TRIF deficiency in LPS-inducible gene expression. Experiment Overall Design: Peritoneal macrophages from wild-type, MyD88-/- and TRIF-/- mice were stimulated with LPS for 0, 1 and 4 hours, followed by RNA extraction. Then hybridization on affymetrix microarrays was performed.
2009-03-01 | E-GEOD-14890 | biostudies-arrayexpress