<i>Helicobacter</i>
            species are potent drivers of colonic T cell responses in homeostasis and inflammation

Chai, Jiani N.; Peng, Yangqing; Rengarajan, Sunaina; Solomon, Benjamin D.; Ai, Teresa L.; Shen, Zeli; Perry, Justin S. A.; Knoop, Kathryn A.; Tanoue, Takeshi; Narushima, Seiko; Honda, Kenya; Elson, Charles O.; Newberry, Rodney D.; Stappenbeck, Thaddeus S.; Kau, Andrew L.; Peterson, Daniel A.; Fox, James G.; Hsieh, Chyi Song

doi:10.1126/sciimmunol.aal5068

Cited by 118 publications

(84 citation statements)

References 66 publications

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“…Commensal microbe-specific T cells can thus acquire pro-inflammatory phenotypes during enteric infection 15 , although the high frequency of such infections suggests the existence of a mechanism to re-establish gut tolerance. Our observations of H. hepaticus -specific iT reg -T H 17 skewing during colitis are consistent with a contemporaneous study using two different Helicobacter species 16 . These findings indicate that dysregulated T cell tolerance to pathobionts may be a general hallmark of IBD.…”

Section: Main Textsupporting

confidence: 91%

c-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont

Pokrovskii

Ding

et al. 2018

Nature

418

412

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Both microbial and host genetic factors contribute to the pathogenesis of autoimmune disease1–4. 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 pathobionts4–6. However, an understanding of how such T cells are constrained in healthy individuals is lacking. Here we report that host tolerance to a potentially pathogenic bacterium, Helicobacter hepaticus (H. hepaticus), is mediated by induction of RORγt+Foxp3+ regulatory T cells (iTreg) that selectively restrain pro-inflammatory TH17 cells and whose function is dependent on the transcription factor c-Maf. Whereas H. hepaticus colonization of wild-type mice promoted differentiation of RORγt-expressing microbe-specific iTreg in the large intestine, in disease-susceptible IL-10-deficient animals there was instead expansion of colitogenic TH17 cells. Inactivation of c-Maf in the Treg compartment likewise impaired differentiation and function, including IL-10 production, of bacteria-specific iTreg, resulting in accumulation of H. hepaticus-specific inflammatory TH17 cells and spontaneous colitis. In contrast, RORγt inactivation in Treg only had a minor effect on bacterial-specific Treg-TH17 balance, and did not result in inflammation. Our results suggest that pathobiont-dependent IBD is driven by microbiota-reactive T cells that have escaped this c-Maf-dependent mechanism of iTreg-TH17 homeostasis.

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Section: Main Textsupporting

confidence: 91%

c-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont

Pokrovskii

Ding

et al. 2018

Nature

418

412

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“…These niches are endowed with specialized antigen-presenting cells—including CD103 + CD11c + dendritic cells in the gut and alveolar and interstitial macrophages in the lung—that polarize antigen-responsive T cells into iTreg cells under the influence of transforming growth factor beta 1 (TGF-β1) and retinoic acid produced by the antigen-presenting cells ( Figure 2 ) 37 – 41 . In the intestine, iTreg cells develop primarily in response to the gut microbiota and food antigens, enabling tolerance to both sets of foreign antigens 42 – 44 . In germ-free (GF) mice, colonic Treg cells generated in the periphery (iTreg cells) are greatly reduced in numbers, reflecting the critical role of colonic bacteria in promoting colonic Treg cell development 45 .…”

Section: What Are the Niches That Promote Antigen-specific Regulatorymentioning

confidence: 99%

Antigen-specific Treg cells in immunological tolerance: implications for allergic diseases

2018

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Allergic diseases are chronic inflammatory disorders in which there is failure to mount effective tolerogenic immune responses to inciting allergens. The alarming rise in the prevalence of allergic diseases in recent decades has spurred investigations to elucidate the mechanisms of breakdown in tolerance in these disorders and means of restoring it. Tolerance to allergens is critically dependent on the generation of allergen-specific regulatory T (Treg) cells, which mediate a state of sustained non-responsiveness to the offending allergen. In this review, we summarize recent advances in our understanding of mechanisms governing the generation and function of allergen-specific Treg cells and their subversion in allergic diseases. We will also outline approaches to harness allergen-specific Treg cell responses to restore tolerance in these disorders.

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“…Mucosal-associated Helicobacter spp. can elicit the differentiation of CD4 + regulatory T cells from peripheral T reg cells in a murine system [39]. Similarly, cluster XIVa Clostridia induce T reg function and density in a murine model of colitis [40], and a cocktail of Clostridia from humans, which included Clostridium cluster XIVa, attenuated murine colitis and allergic diarrhea, also via T reg induction [41].…”

Section: Plos Neglected Tropical Diseasesmentioning

confidence: 99%

Growth velocity in children with Environmental Enteric Dysfunction is associated with specific bacterial and viral taxa of the gastrointestinal tract in Malawian children

et al. 2020

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Environmental enteric dysfunction (EED) is characterized by diffuse villous atrophy of the small bowel. EED is strongly associated with stunting, a major public health problem linked to increased childhood morbidity and mortality. EED and subsequent stunting of linear growth are surmised to have microbial origins. To interrogate this relationship, we defined the comprehensive virome (eukaryotic virus and bacteriophage) and bacterial microbiome of a longitudinal cohort of rural Malawian children with extensive metadata and intestinal permeability testing at each time point. We found thirty bacterial taxa differentially associated with linear growth. We detected many eukaryotic viruses. Neither the total number of eukaryotic families nor a specific viral family was statistically associated with improved linear growth. We identified 3 differentially abundant bacteriophage among growth velocities. Interestingly, there was a positive correlation between bacteria and bacteriophage richness in children with subsequent adequate/moderate growth which children with subsequent poor growth lacked. This suggests that a disruption in the equilibrium between bacteria and bacteriophage communities might be associated with subsequent poor growth. Future studies of EED and stunting should include the evaluation of viral communities in addition to bacterial microbiota to understand the complete microbial ecology of these poorly understood entities.

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Helicobacter species are potent drivers of colonic T cell responses in homeostasis and inflammation

Cited by 118 publications

References 66 publications

c-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont

c-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont

Antigen-specific Treg cells in immunological tolerance: implications for allergic diseases

Growth velocity in children with Environmental Enteric Dysfunction is associated with specific bacterial and viral taxa of the gastrointestinal tract in Malawian children

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