C-Maf-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont
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ABSTRACT:
PROVIDER: PRJNA422768 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6384660_1.fastq.gz | Fastqsanger.gz | |||
| SRR6384660_2.fastq.gz | Fastqsanger.gz | |||
| SRR6384670_1.fastq.gz | Fastqsanger.gz | |||
| SRR6384670_2.fastq.gz | Fastqsanger.gz | |||
| SRR6384661_1.fastq.gz | Fastqsanger.gz |
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Project description:Both microbial and host genetic factors contribute to the pathogenesis of autoimmune disease. Accumulating evidence suggests that microbial species that potentiate chronic inflammation, as in inflammatory bowel disease (IBD), often also colonize healthy individuals. These microbes, including the Helicobacter species, have the propensity to induce pathogenic T cells and are collectively referred to as pathobionts. However, an understanding of how such T cells are constrained in healthy individuals is lacking. For this study we wanted to compare the transcriptomes of H. hepaticus-specific T effector cells from mice that were IL-10-deficient to those that were Maf-deficient in the Treg compartment to determine if they share an inflammatory signature. We also compared Maf -sufficient and -deficient polyclonal iTreg to determine molecular targets of the TF c-Maf.
2017-12-19 | GSE108184 | GEO
Project description:Both microbial and host genetic factors contribute to the pathogenesis of autoimmune diseases. There is accumulating evidence that microbial species that potentiate chronic inflammation, as in inflammatory bowel disease, often also colonize healthy individuals. These microorganisms, including the Helicobacter species, can induce pathogenic T cells and are collectively referred to as pathobionts. However, how such T cells are constrained in healthy individuals is not yet understood. Here we report that host tolerance to a potentially pathogenic bacterium, Helicobacter hepaticus, is mediated by the induction of RORγt+FOXP3+ regulatory T (iTreg) cells that selectively restrain pro-inflammatory T helper 17 (TH17) cells and whose function is dependent on the transcription factor c-MAF. Whereas colonization of wild-type mice by H. hepaticus promoted differentiation of RORγt-expressing microorganism-specific iTreg cells in the large intestine, in disease-susceptible IL-10-deficient mice, there was instead expansion of colitogenic TH17 cells. Inactivation of c-MAF in the Treg cell compartment impaired differentiation and function, including IL-10 production, of bacteria-specific iTreg cells, and resulted in the accumulation of H. hepaticus-specific inflammatory TH17 cells and spontaneous colitis. By contrast, RORγt inactivation in Treg cells had only a minor effect on the bacteria-specific Treg and TH17 cell balance, and did not result in inflammation. Our results suggest that pathobiont-dependent inflammatory bowel disease is driven by microbiota-reactive T cells that have escaped this c-MAF-dependent mechanism of iTreg-TH17 homeostasis.
| S-EPMC5814346 | biostudies-literature
Project description:c-Maf-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont
| PRJNA421991 | ENA
Project description:Using single-cell RNA-seq of colon lamina propria leukocytes (LPL), together with ATAC-seq, ChIP-seq and RNA-seq from colon LPL and sorted CD4+ T from colon lamina propria during oral infection with the pathobiont Helicobacter hepaticus we show that Blimp-1 and c-Maf both positively regulate Il10 gene expression, but also cooperate to negatively regulate a large network of proinflammatory effector genes in T cells. While T cell-specific deletion of either Prdm1, Maf or both transcription factors did not result in overt inflammation of the colon at steady state, H. hepaticus infection resulted in mild/moderate colitis in both the Prdm1fl/flCd4Cre and Maffl/flCd4Cre single T cell-specific transcription factor deficient mice, while the double knockout Prdm1fl/flMaffl/flCd4Cre infected mice suffered severe colitis and showed a massive increase in T cell effector genes in colonic LPL. Blimp-1 and c-Maf cooperate to negatively regulate genes including Ifng, Csf2, Il23r, Stat4, Il18r1 and Il2rg, and deletion of both these transcription factors in T cells translated to an exacerbated pathogenic TH1, IFN-g+GM-CSF+ effector cell response. c-Maf, additionally negatively regulated Il17a expression which was elevated in the LPL as assessed by bulk RNA-seq and scRNA-Seq analysis in the H. hepaticus infected Maffl/flCd4Cre mice.
2024-02-18 | GSE240421 | GEO
Project description:Using single-cell RNA-seq of colon lamina propria leukocytes (LPL), together with ATAC-seq, ChIP-seq and RNA-seq from colon LPL and sorted CD4+ T from colon lamina propria during oral infection with the pathobiont Helicobacter hepaticus we show that Blimp-1 and c-Maf both positively regulate Il10 gene expression, but also cooperate to negatively regulate a large network of proinflammatory effector genes in T cells. While T cell-specific deletion of either Prdm1, Maf or both transcription factors did not result in overt inflammation of the colon at steady state, H. hepaticus infection resulted in mild/moderate colitis in both the Prdm1fl/flCd4Cre and Maffl/flCd4Cre single T cell-specific transcription factor deficient mice, while the double knockout Prdm1fl/flMaffl/flCd4Cre infected mice suffered severe colitis and showed a massive increase in T cell effector genes in colonic LPL. Blimp-1 and c-Maf cooperate to negatively regulate genes including Ifng, Csf2, Il23r, Stat4, Il18r1 and Il2rg, and deletion of both these transcription factors in T cells translated to an exacerbated pathogenic TH1, IFN-g+GM-CSF+ effector cell response. c-Maf, additionally negatively regulated Il17a expression which was elevated in the LPL as assessed by bulk RNA-seq and scRNA-Seq analysis in the H. hepaticus infected Maffl/flCd4Cre mice.
2024-02-18 | GSE240420 | GEO
Project description:Using single-cell RNA-seq of colon lamina propria leukocytes (LPL), together with ATAC-seq, ChIP-seq and RNA-seq from colon LPL and sorted CD4+ T from colon lamina propria during oral infection with the pathobiont Helicobacter hepaticus we show that Blimp-1 and c-Maf both positively regulate Il10 gene expression, but also cooperate to negatively regulate a large network of proinflammatory effector genes in T cells. While T cell-specific deletion of either Prdm1, Maf or both transcription factors did not result in overt inflammation of the colon at steady state, H. hepaticus infection resulted in mild/moderate colitis in both the Prdm1fl/flCd4Cre and Maffl/flCd4Cre single T cell-specific transcription factor deficient mice, while the double knockout Prdm1fl/flMaffl/flCd4Cre infected mice suffered severe colitis and showed a massive increase in T cell effector genes in colonic LPL. Blimp-1 and c-Maf cooperate to negatively regulate genes including Ifng, Csf2, Il23r, Stat4, Il18r1 and Il2rg, and deletion of both these transcription factors in T cells translated to an exacerbated pathogenic TH1, IFN-g+GM-CSF+ effector cell response. c-Maf, additionally negatively regulated Il17a expression which was elevated in the LPL as assessed by bulk RNA-seq and scRNA-Seq analysis in the H. hepaticus infected Maffl/flCd4Cre mice.
2024-02-18 | GSE240419 | GEO
Project description:Using single-cell RNA-seq and bulk tissue RNA-seq of colon lamina propria leukocytes (LPL), together with ATAC-seq, ChIP-seq and RNA-seq from colon LPL and sorted CD4+ T from colon lamina propria during oral infection with the pathobiont Helicobacter hepaticus we show that Blimp-1 and c-Maf both positively regulate Il10 gene expression, but also cooperate to negatively regulate a large network of proinflammatory effector genes in T cells. While T cell-specific deletion of either Prdm1, Maf or both transcription factors did not result in overt inflammation of the colon at steady state, H. hepaticus infection resulted in mild/moderate colitis in both the Prdm1fl/flCd4Cre and Maffl/flCd4Cre single T cell-specific transcription factor deficient mice, while the double knockout Prdm1fl/flMaffl/flCd4Cre infected mice suffered severe colitis and showed a massive increase in T cell effector genes in colonic LPL. Blimp-1 and c-Maf cooperate to negatively regulate genes including Ifng, Csf2, Il23r, Stat4, Il18r1 and Il2rg, and deletion of both these transcription factors in T cells translated to an exacerbated pathogenic TH1, IFN-g+GM-CSF+ effector cell response. c-Maf, additionally negatively regulated Il17a expression which was elevated in the LPL as assessed by bulk RNA-seq and scRNA-Seq analysis in the H. hepaticus infected Maffl/flCd4Cre mice.
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Project description:Maintenance of immunological homeostasis between tolerance and autoimmunity is essential for the prevention of human diseases ranging from autoimmune disease to cancer. Accumulating evidence suggests that p53 can mitigate phagocytosis-induced adjuvanticity thereby promoting immunological tolerance following programmed cell death. Here we identify Inhibitor of Apoptosis Stimulating p53 Protein (iASPP), a negative regulator of p53 transcriptional activity, as a regulator of immunological tolerance. iASPP-deficiency promoted lung adenocarcinoma and pancreatic cancer tumorigenesis, while iASPP-deficient mice were less susceptible to autoimmune disease. Immune responses to iASPP-deficient tumors exhibited hallmarks of immunosuppression, including activated regulatory T cells and exhausted CD8+ T cells. Interestingly, iASPP-deficient tumor cells and tumor-infiltrating myeloid cells, CD4+, and gd T cells expressed elevated levels of PD-1H, a recently identified transcriptional target of p53 that promotes tolerogenic phagocytosis. Identification of an iASPP/p53 axis of immune homeostasis provides a therapeutic opportunity for both autoimmune disease and cancer.
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Project description:Maintenance of immunological homeostasis between tolerance and autoimmunity is essential for the prevention of human diseases ranging from autoimmune disease to cancer. Accumulating evidence suggests that p53 can mitigate phagocytosis-induced adjuvanticity thereby promoting immunological tolerance following programmed cell death. Here we identify Inhibitor of Apoptosis Stimulating p53 Protein (iASPP), a negative regulator of p53 transcriptional activity, as a regulator of immunological tolerance. iASPP-deficiency promoted lung adenocarcinoma and pancreatic cancer tumorigenesis, while iASPP-deficient mice were less susceptible to autoimmune disease. Immune responses to iASPP-deficient tumors exhibited hallmarks of immunosuppression, including activated regulatory T cells and exhausted CD8+ T cells. Interestingly, iASPP-deficient tumor cells and tumor-infiltrating myeloid cells, CD4+, and γδ T cells expressed elevated levels of PD-1H, a recently identified transcriptional target of p53 that promotes tolerogenic phagocytosis. Identification of an iASPP/p53 axis of immune homeostasis provides a therapeutic opportunity for both autoimmune disease and cancer.
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