Gut intraepithelial T cells calibrate metabolism and accelerate cardiovascular disease

He, Shasha; Kahles, Florian; Rattik, Sara; Nairz, Manfred; McAlpine, Cameron S.; Anzai, Atsushi; Selgrade, Daniel; Fenn, Ashley M.; Chan, Christopher T.; Mindur, John E.; Valet, Colin; Poller, Wolfram C.; Halle, Lennard; Rotllan, Noemí; Iwamoto, Yoshiko; Wojtkiewicz, Gregory R.; Weissleder, Ralph; Libby, Peter; Fernández‐Hernando, Carlos; Drucker, Daniel J.; Nahrendorf, Matthias; Świrski, Filip K.

doi:10.1038/s41586-018-0849-9

Cited by 119 publications

(119 citation statements)

References 31 publications

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“…IETs are tissue-resident cells that respond to foreign antigen from the intestinal lumen and to self-derived, stress-induced molecules, positioning IETs as first responders to enteric pathogens or as mediators of epithelial stress, respectively (2)(3)(4)(5). IETs are also important in regulating metabolism; mice lacking IETs are resistant to weight gain, even when fed a high-fat diet, due to a hyperactive metabolic profile, indicating IETs have an important role in promoting weight gain efficiency (6). In the context of immunity, IETs can release cytotoxic molecules, cytokines, and/or antimicrobial peptides upon activation, inducing intestinal inflammation and/or antimicrobial activity associated with immune protection (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

“…Hence, IETs are critical in balancing immune tolerance and protection within the intestinal tract. Moreover, microbial and dietary antigen exposure majorly influence the development, specificity, reactivity, and homeostasis of IETs (6,(10)(11)(12)(13)(14), largely contributing to their fate in promoting or deteriorating intestinal health (2).…”

Section: Introductionmentioning

confidence: 99%

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Intraepithelial T cells diverge by intestinal location as pigs age

Wiarda

Trachsel

Bond

et al. 2020

Preprint

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T cells resident within the intestinal epithelium play a central role in barrier integrity and provide a first line of immune defense. Intraepithelial T cells (IETs) are among the earliest immune cells to populate and protect intestinal tissues, thereby giving them an important role in shaping gut health early in life. In pigs, IETs are poorly defined, and their maturation in young pigs has not been well studied. Given the importance of IETs in contributing to early life and long-term intestinal health through interactions with epithelial cells, the microbiota, and additional environmental factors, a deeper characterization of IETs in pigs is warranted. The objective of this study was to analyze age-and intestinal location-dependent changes in IETs across multiple sites of the small and large intestine in pigs between 4 and 8 weeks of age. IETs increased in abundance over time and belonged to both γδ and αβ T cell lineages. Similar compositions of IETs were identified across intestinal sites in 4-week-old pigs, but compositions diverged between intestinal sites as pigs aged. CD2 + CD8α + γδ T cells and CD4 -CD8α + αβ T cells comprised >78% of total IETs at all intestinal locations and ages examined. Greater percentages of γδ IETs were present in large intestine compared to small intestine in older pigs. Small intestinal tissues had greater percentages of CD2 + CD8αγδ IETs, while CD2 + CD8α + γδ IET percentages were greater in the large intestine. Percentages of CD4 -CD8α + αβ IETs increased over time across all intestinal sites. Moreover, percentages of CD27 + cells decreased in ileum and large intestine over time, indicating increased IET activation as pigs aged. Percentages of CD27 + cells were also higher in small intestine compared to large intestine at later timepoints.Results herein emphasize 4 to 8 weeks of age as a critical window of IET maturation and suggest strong associations between intestinal location and age with IET heterogeneity in pigs.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Intraepithelial T cells diverge by intestinal location as pigs age

Wiarda

Trachsel

Bond

et al. 2020

Preprint

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“…Furthermore, administration of an antibody against αEβ7 attenuated immunization‐induced colitis in IL‐2–deficient mice, providing additional evidence that αEβ7 is an important player in the inflammatory processes associated with IBD pathogenesis . In addition to immune functions, a study in mice showed that β7 + IELs also calibrate metabolism by binding GLP‐1 and limiting its systemic availability, suggesting potential added benefit of β7 blockade …”

Section: A Model For Integrins and T Lymphocytes As Therapeutic Targementioning

confidence: 97%

“…89 In addition to immune functions, a study in mice showed that β7 + IELs also calibrate metabolism by binding GLP-1 and limiting its systemic availability, suggesting potential added benefit of β7 blockade. 129 The efficacy of etrolizumab in patients with UC was demonstrated in the phase 2 EUCALYPTUS study which showed higher rates of remission at week 10 and similar frequency of adverse events compared with placebo, 130 establishing the therapeutic potential of targeting both α4β7 and αEβ7 with anti-integrin therapy. Furthermore, in etrolizumab-treated patients, αEβ7 + cells in the intestinal epithelium were reduced in comparison with the placebo group, with no observed decrease in αEβ7 + cells in the lamina propria in either treatment group, indicating that binding of etrolizumab to αEβ7 cells was preventing these cells from binding E-cadherin and being retained in the epithelium.…”

mentioning

confidence: 99%

The role of integrins in the pathogenesis of inflammatory bowel disease: Approved and investigational anti‐integrin therapies

Dotan

Allez

Danese

et al. 2019

Medicinal Research Reviews

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Inflammatory bowel disease (IBD) is characterized by uncontrolled inflammation in the gastrointestinal tract. The underlying pathobiology of IBD includes an increase in infiltrating gut‐homing lymphocytes. Although lymphocyte homing is typically a tightly regulated and stepwise process involving multiple integrins and adhesion molecules expressed on endothelial cells, the distinct roles of integrin‐expressing immune cells is not fully understood in the pathology of IBD. In this review, we detail the involvement of integrins expressed on specific lymphocyte subsets in the pathogenesis of IBD and discuss the current status of approved and investigational integrin‐targeted therapies.

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“…Previously proposed mechanisms have centered around crosstalk with the gut microbiome and the immune system's ability to modify intestinal barrier function or maintain tolerance to luminal antigen (Winer et al, 2016). However, in a recent Letter published in Nature, He et al describe an exciting intestinal T cell-incretin axis that provides new insight into gut resident immune cells' capacity to regulate whole-body metabolism with important effects on metabolic syndrome (He et al, 2019).…”

mentioning

confidence: 99%