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Gastrointestinal γδ T cells reveal differentially expressed transcripts and enriched pathways during peanut oral immunotherapy

Wiley
Allergy
Authors:
  • Imperial College of London
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    LET TERS
Takeya Adachi and Yasushi Ogawa authors contributed equally to
this work
ORCID
Takeya Adachi https://orcid.org/0000-0002-5289-5980
Yasushi Ogawa https://orcid.org/0000-0003-3553-9607
Tamami Fukushi https://orcid.org/0000-0003-4599-2413
Amane Koizumi https://orcid.org/0000-0003-1177-0185
Masashi Shirabe https://orcid.org/0000-0003-4569-6171
Masako Toriya https://orcid.org/0000-0002-8955-0353
Takenori Inomata https://orcid.org/0000-0003-3435-1055
Katsunori Masaki https://orcid.org/0000-0003-0909-9409
Sakura Sato https://orcid.org/0000-0003-3674-0759
Masaki Futamura https://orcid.org/0000-0002-7442-9649
Keiko Kan- o https://orcid.org/0000-0002-7736-588X
Yosuke Kurashima https://orcid.org/0000-0001-8588-4033
Saeko Nakajima https://orcid.org/0000-0003-0831-1447
Hideaki Morita https://orcid.org/0000-0003-0928-8322
Aikichi Iwamoto https://orcid.org/0000-0001-5868-7499
Mayumi Tamari https://orcid.org/0000-0002-5755-9177
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SUPPORTING INFORMATION
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version of the article at the publisher’s website.
DOI : 10.1111/all.1 5250
Gastrointestinal γδ T cells reveal differentially expressed
transcripts and enriched pathways during peanut oral
immunotherapy
To the Editor,
Oral immunotherapy (OIT) has been successful in desensitizing
patients to offending food allergens,1 although the identification
of tissue- resident T- cell subsets and cognate pathways leading to
desensitization has been challenging. The γδ T cells are a major T-
cell subset of mucosal intraepithelial lymphocytes (IELs) and play a
significant role in tissue homeostasis and repair.2 In addition to aid-
ing mucosal barrier function, γδ T cells have also been recently dis-
covered to be pivotal to cellular adaptations in response to nutrient
sensing.3 In the broader context of atopy, γδ T cells have been impli-
cated both in IgE- and Th2- enhancing and IgE- suppressive effects.4,5
However, specifically with regard to peanut allerg y, γδ T cells were
shown to be IgE- suppressive and thus protective in a study employ-
ing mouse models.6 In a recent study, peripheral γδ Treg cells from
patients analyzed over 24 weeks of peanut OIT were shown to un-
dergo dynamic changes in expression profiles, implicating pathways
involved in immune homeostasis.7 To the best of our knowledge, the
role of γδ T cells in the intestinal mucosa of food allergic patients dur-
ing immunotherapy has not been examined. To this end, we inves-
tigated whether γδ T cells in the gastrointestinal (GI) tract exhibited
changes during peanut OIT. We hypothesized that GI- resident γδ T
cells in peanut allergic patients would increase during the course of
peanut OIT and might reveal transcripts and pathways relevant to
the mechanisms of peanut desensitization.
Participants were recruited from a randomized, double- blind,
placebo- controlled, phase II clinical trial of peanut OIT (POISED;
NCT02103270).1 Informed consent was obtained from all partici-
pants. Following dosage build- up over ~52 weeks, peanut- allergic
Nadeau, Manohar, DeKruyff and Chinthrajah are Co- senior authors.
Article
Full-text available
The prevalence of food allergy continues to rise globally, carrying with it substantial safety, economic, and emotional burdens. Although preventative strategies do exist, the heterogeneity of allergy trajectories and clinical phenotypes has made it difficult to identify patients who would benefit from these strategies. Therefore, further studies investigating the molecular mechanisms that differentiate these trajectories are needed. Large-scale omics studies have identified key insights into the molecular mechanisms for many different diseases, however the application of these technologies to uncover the drivers of food allergy development is in its infancy. Here we review the use of omics approaches in food allergy and highlight key gaps in knowledge for applying these technologies for the characterization of food allergy development.
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Food allergies affect up to 10% of the US population, can be life-threatening, and have a significant negative impact on quality of life. Delayed dietary introduction of foods in childhood can hinder the induction of oral tolerance, an active regulatory response to foods that prevents the development of food allergy. Some children outgrow their food allergies naturally, while many others have persistent, lifelong food allergy for which there are few therapeutic options. Oral immunotherapy (OIT) is a therapeutic approach of giving increasing amounts of food to attempt to desensitize the allergic individual. In this review, we focus on the immune mechanisms common to oral tolerance and response to oral immunotherapy, with the objective of determining whether true tolerance can be achieved after food allergy has been established.
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Background Peanut oral immunotherapy (POIT) has provided desensitization to peanut allergic individuals. Limited immunological evaluation exists during the first 24-weeks of POIT. Objective Regulatory T-cells (Tregs) are antigen induced immunosuppressive T-cells important in establishing tolerance. Delineation of early immunologic changes contributing to the development of peanut desensitization would help clarify the mechanism of action in POIT. We performed single-cell RNA sequencing (scRNAseq) on Tregs in pediatric subjects undergoing POIT during the first 24-weeks of therapy to evaluate early immunological changes induced by POIT. Methods PBMC samples from peanut allergic subjects between 5 and 12 years of age enrolled in a Phase 1/2a POIT study were collected and analyzed at 0, 6, and 24-weeks after POIT initiation and samples were compared to healthy non-peanut allergic controls. Tregs were enriched from PBMCs and scRNAseq analysis performed. Cell Ranger 3.1.0 (10× Genomics) was utilized to identify cell clusters and differentially expressed genes, and results were analyzed with Seurat suite version 3.0.0. Results Gene analysis revealed 10 major clusters corresponding to different cell types observed to change during POIT when compared to the healthy, non-peanut-allergic state. scRNAseq analysis of Tregs revealed strong CD3G expression correlating with gdTregs. scRNAseq analysis of gdTregs revealed dynamic changes occurring within the first 6-weeks of treatment and cell frequencies of naïve and memory gdTregs at 24-weeks of treatment reducing to levels similar to healthy controls. Analysis of transcriptomic cell identity analysis using SingleR showed gene expression in gdTregs similar to healthy control after 24-weeks of POIT treatment. scRNAseq analysis revealed alterations in gene expression for memory and naïve gdTregs during this timeframe. Specifically, expression of OX40R (TNFRSF4), GITR (TNFRSF18), TGFB1, CTLA4, ISG20, CD69 were upregulated in memory gdTregs compared to naive gdTregs by 24-weeks of POIT, while IL7R and SELL were downregulated in memory gdTregs compared to naïve gdTregs. Conclusions There are specific expression profiles of peripheral naïve and mature gdTreg cells in peanut allergic patients undergoing POIT in the first 24-weeks of treatment implicating pathways involved in maintenance of immune homeostasis. gdTreg cells may contribute to the tolerogenic effect of POIT within the first 24-weeks of POIT treatment. These findings suggest that gdTregs cells may be an early marker of desensitization in subjects undergoing POIT.
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γδ T cells link immunity to nutrition Gamma delta (γδ) T cells are immune cells best known for host barrier defenses in epithelial tissues. Sullivan et al. discovered a previously unrecognized role for γδ T cells in sensing nutrient uptake in the small intestine (see the Perspective by Talbot and Littman). The researchers analyzed mice fed a high-carbohydrate versus a high-protein diet and observed remodeling of the small intestinal epithelium in response to dietary carbohydrates. Nutrient availability triggered an epithelial–immune cell circuit that was required for digestion and absorption of carbohydrates. Intestinal γδ T cells regulated the expression of a carbohydrate transcriptional program by limiting interleukin-22 production from type 3 innate lymphoid cells. These findings may also provide insights into how γδ T cells modulate metabolic disease. Science , this issue p. eaba8310 ; see also p. 1202
Article
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