T-cell expression of AhR inhibits the maintenance of pTreg cells in the gastrointestinal tract in acute GVHD

Dant, Trisha A.; Lin, Kaifeng; Bruce, Danny; Montgomery, Stephanie A.; Kolupaev, Oleg; Bommiasamy, Hemamalini; Bixby, Lisa M.; Woosley, John T.; McKinnon, Karen P.; Gonzalez, Frank J.; Blazar, Bruce R.; Vincent, Benjamin G.; Coghill, James M.; Serody, Jonathan S.

doi:10.1182/blood-2016-08-734244

Cited by 23 publications

(21 citation statements)

References 43 publications

(56 reference statements)

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“…in the infant gut contribute to innate protection against gastrointestinal pathogens. Further, AhR ligands (including ILA) have been shown to modulate the adaptive immune system by promoting IL-10+T reg induction and suppressing IL-17 and IFNγ production by T-cells, potentially reducing the risk of autoimmunity 52–54 . Non-AhR mediated mechanisms may add to the protective effect, as ILA and PLA have been shown in vitro to have direct anti-bacterial 55, 56 and anti-fungal properties 57, 58 .…”

Section: Discussionmentioning

confidence: 99%

Breastmilk-promoted bifidobacteria produce aromatic amino acids in the infant gut

Laursen

Sakanaka

Burg

et al. 2020

Preprint

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26Breastfeeding profoundly shapes the infant gut microbiota, which is critical for early life immune 27 development. However, few breastmilk-dependent microbial metabolites mediating host-microbiota 28 interactions are currently known. We here demonstrate that breastmilk-promoted Bifidobacterium 29 species convert aromatic amino acids (tryptophan, phenylalanine and tyrosine) into their respective 30 aromatic lactic acids (indolelactate, phenyllactate and 4-hydroxyphenyllactate) via a previously 31 unrecognised aromatic lactate dehydrogenase. By longitudinal profiling of the gut microbiota 32 composition and metabolome of stool samples of infants obtained from birth until 6 months of age, 33 we show that stool concentrations of aromatic lactic acids is determined by the abundance of human 34 milk oligosaccharide degrading Bifidobacterium species containing the aromatic lactate 35 dehydrogenase. Finally, we demonstrate that stool concentrations of Bifidobacterium-derived 36 indolelactate are associated with the capacity of infant stool samples to activate the aryl 37 hydrocarbon receptor, a receptor important for maintenance of intestinal homeostasis and immune 38 system development. These findings open up new directions towards understanding the role of 39 breastmilk-promoted Bifidobacterium in mediating host-microbiota interactions in early life. 40 INTRODUCTION 41Human breastmilk is a perfectly adapted nutritional supply for the infant 1 . Breastfeeding provides 42 children with important short-term protection against infections, and may also provide long-term 43 metabolic benefits 1,2 . These benefits may partly be mediated through the gut microbiota, since 44 breastfeeding is the strongest determinant of gut microbiota composition and function during 45 infancy 3-5 . Human breastmilk contains human milk oligosaccharides (HMOs), which are complex, 46 highly abundant sugars serving as substrates for specific microbes including certain species of 47 Bifidobacterium 6 . This co-evolution between bifidobacteria and the host, mediated by HMOs, to a 48 large extent directs the colonization of the gut in early life, which has critical impact on the immune 49 system 7 . Depletion of specific microbes, including Bifidobacterium, in early life has been associated 50 with increased risk of allergy and asthma development in childhood 8,9 , and is suggested to 51 compromise immune function and lead to increased susceptibility to infectious disease 10,11 . Despite 52 Bifidobacterium dominating the gut of breastfed infants and being widely acknowledged as 53 beneficial, mechanistic insights on the contribution of these bacteria and their metabolites to 54 immune development during infancy remain limited. Recent studies show that microbial aromatic 55 amino acid metabolites including tryptophan-derived indoles 12 , via activation of the aryl 56 hydrocarbon receptor (AhR), can fortify the intestinal barrier 13,14 , protect against pathogenic 57 infections 15,16 and influence host metabolism 13,17,18 , which makes this...

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Section: Discussionmentioning

confidence: 99%

Breastmilk-promoted bifidobacteria produce aromatic amino acids in the infant gut

Laursen

Sakanaka

Burg

et al. 2020

Preprint

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“…AhR activation is protective in colitis by regulating intestinal crypt stem cell differentiation (36). AhR signaling can also drive immune responses in favor of either regulatory T cell or Th17 differentiation, suggesting ligand-and cell type-specific effects that could either ameliorate or worsen aGVHD (37,38). AREG is similarly protective in models of colitis and associated with Treg-and T9-mediated tissue repair (39)(40)(41)(42)(43).…”

Section: Top Go Biological Processes Differentiating Onset Agvhd Vementioning

confidence: 99%

Stress responses, M2 macrophages, and a distinct microbial signature in fatal intestinal acute graft-versus-host disease

Holtan¹,

Shabaneh²,

Betts³

et al. 2019

JCI Insight

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“…In contrast, the expression of multiple cytokines (Ifng, Il17f, Il21, Il22) and cytokine receptors (Il1r1, Il23r) with a reported role in GVHD (70-74) was downregulated early on by Dll1/4 inhibition. Notch blockade also downregulated the expression of Ahr and Icos (75,76), identified as therapeutic targets in GVHD. Additional gene expression changes could be related mechanistically to the observed GVHD abrogation.…”

Section: Discussionmentioning

confidence: 97%

Early Notch Signals Induce a Pathogenic Molecular Signature during Priming of Alloantigen-Specific Conventional CD4+ T Cells in Graft-versus-Host Disease

Chung

Radojčić

Perkey

et al. 2019

The Journal of Immunology

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Graft-versus-host disease (GVHD) is the most serious complication of allogeneic hematopoietic cell transplantation. Notch signals delivered during the first 48 h after transplantation drive proinflammatory cytokine production in conventional T cells (Tconv) and inhibit the expansion of regulatory T cells (Tregs). Short-term Notch inhibition induces long-term GVHD protection. However, it remains unknown whether Notch blockade blunts GVHD through its effects on Tconv, Tregs, or both and what early Notch-regulated molecular events occur in alloantigen-specific T cells. To address these questions, we engineered T cell grafts to achieve selective Notch blockade in Tconv versus Tregs and evaluated their capacity to trigger GVHD in mice. Notch blockade in Tconv was essential for GVHD protection as GVHD severity was similar in the recipients of wild-type Tconv combined with Notch-deprived versus wild-type Tregs. To identify the impact of Notch signaling on the earliest steps of T cell activation in vivo, we established a new acute GVHD model mediated by clonal alloantigen-specific 4C CD4 + Tconv. Notch-deprived 4C T cells had preserved early steps of activation, IL-2 production, proliferation, and Th cell polarization. In contrast, Notch inhibition dampened IFN-g and IL-17 production, diminished mTORC1 and ERK1/2 activation, and impaired transcription of a subset of Myc-regulated genes. The distinct Notch-regulated signature had minimal overlap with known Notch targets in T cell leukemia and developing T cells, highlighting the specific impact of Notch signaling in mature T cells. Our findings uncover a unique molecular program associated with the pathogenic effects of Notch in T cells at the earliest stages of GVHD.

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T-cell expression of AhR inhibits the maintenance of pTreg cells in the gastrointestinal tract in acute GVHD

Cited by 23 publications

References 43 publications

Breastmilk-promoted bifidobacteria produce aromatic amino acids in the infant gut

Breastmilk-promoted bifidobacteria produce aromatic amino acids in the infant gut

Stress responses, M2 macrophages, and a distinct microbial signature in fatal intestinal acute graft-versus-host disease

Early Notch Signals Induce a Pathogenic Molecular Signature during Priming of Alloantigen-Specific Conventional CD4+ T Cells in Graft-versus-Host Disease

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