Single-cell profiling of peanut-responsive T cells in patients with peanut allergy reveals heterogeneous effector TH2 subsets

David Chiang; Xintong Chen; Stacie M Jones; Robert A Wood; Scott H Sicherer; A Wesley Burks; Donald Y M Leung; Charuta Agashe; Alexander Grishin; Peter Dawson; Wendy F Davidson; Leah Newman; Robert Sebra; Miriam Merad; Hugh A Sampson; Bojan Losic; M Cecilia Berin

doi:10.1016/j.jaci.2017.11.060

Single-cell profiling of peanut-responsive T cells in patients with peanut allergy reveals heterogeneous effector T_H2 subsets

J Allergy Clin Immunol. 2018 Jun;141(6):2107-2120. doi: 10.1016/j.jaci.2017.11.060. Epub 2018 Jan 31.

Authors

David Chiang¹, Xintong Chen², Stacie M Jones³, Robert A Wood⁴, Scott H Sicherer¹, A Wesley Burks⁵, Donald Y M Leung⁶, Charuta Agashe¹, Alexander Grishin¹, Peter Dawson⁷, Wendy F Davidson⁸, Leah Newman², Robert Sebra², Miriam Merad⁹, Hugh A Sampson¹, Bojan Losic¹⁰, M Cecilia Berin¹¹

Affiliations

¹ Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY.
² Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.
³ Department of Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children's Hospital, Little Rock, Ark.
⁴ Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Md.
⁵ Department of Pediatrics, University of North Carolina, Chapel Hill, NC.
⁶ Department of Pediatrics, National Jewish Health, Denver, Colo.
⁷ EMMES Corporation, Rockville, Md.
⁸ National Institutes of Health (National Institute of Allergy and Infectious Diseases), Bethesda, Md.
⁹ Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.
¹⁰ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY. Electronic address: bojan.losic@mssm.edu.
¹¹ Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY. Electronic address: cecilia.berin@mssm.edu.

Abstract

Background: The contribution of phenotypic variation of peanut-specific T cells to clinical allergy or tolerance to peanut is not well understood.

Objectives: Our objective was to comprehensively phenotype peanut-specific T cells in the peripheral blood of subjects with and without peanut allergy (PA).

Methods: We obtained samples from patients with PA, including a cohort undergoing baseline peanut challenges for an immunotherapy trial (Consortium of Food Allergy Research [CoFAR] 6). Subjects were confirmed as having PA, or if they passed a 1-g peanut challenge, they were termed high-threshold subjects. Healthy control (HC) subjects were also recruited. Peanut-responsive T cells were identified based on CD154 expression after 6 to 18 hours of stimulation with peanut extract. Cells were analyzed by using flow cytometry and single-cell RNA sequencing.

Results: Patients with PA had tissue- and follicle-homing peanut-responsive CD4⁺ T cells with a heterogeneous pattern of T_H2 differentiation, whereas control subjects had undetectable T-cell responses to peanut. The PA group had a delayed and IL-2-dependent upregulation of CD154 on cells expressing regulatory T (Treg) cell markers, which was absent in HC or high-threshold subjects. Depletion of Treg cells enhanced cytokine production in HC subjects and patients with PA in vitro, but cytokines associated with highly differentiated T_H2 cells were more resistant to Treg cell suppression in patients with PA. Analysis of gene expression by means of single-cell RNA sequencing identified T cells with highly correlated expression of IL4, IL5, IL9, IL13, and the IL-25 receptor IL17RB.

Conclusions: These results demonstrate the presence of highly differentiated T_H2 cells producing T_H2-associated cytokines with functions beyond IgE class-switching in patients with PA. A multifunctional T_H2 response was more evident than a Treg cell deficit among peanut-responsive T cells.

Trial registration: ClinicalTrials.gov NCT01904604.

Keywords: Food allergy; T(H)2; peanut allergy; regulatory T; tolerance.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Female
Humans
Male
Peanut Hypersensitivity / immunology*
Randomized Controlled Trials as Topic
T-Lymphocyte Subsets / immunology*
Th2 Cells / immunology*
Young Adult

Associated data

ClinicalTrials.gov/NCT01904604

Abstract

Publication types

MeSH terms

Associated data

Grants and funding