Single-cell profiling of peanut-responsive T cells in patients with peanut allergy reveals heterogeneous effector T                         H                         2 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 _H 2 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

Research output: Contribution to journal › Article › peer-review

76 Scopus citations

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 _H 2 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 _H 2 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 _H 2 cells producing T _H 2-associated cytokines with functions beyond IgE class-switching in patients with PA. A multifunctional T _H 2 response was more evident than a Treg cell deficit among peanut-responsive T cells.

Original language	English
Pages (from-to)	2107-2120
Number of pages	14
Journal	Journal of Allergy and Clinical Immunology
Volume	141
Issue number	6
DOIs	https://doi.org/10.1016/j.jaci.2017.11.060
State	Published - Jun 2018

Keywords

Food allergy
T 2
peanut allergy
regulatory T
tolerance

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10.1016/j.jaci.2017.11.060

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Chiang, D., Chen, X., Jones, S. M., Wood, R. A., Sicherer, S. H., Burks, A. W., Leung, D. Y. M., Agashe, C., Grishin, A., Dawson, P., Davidson, W. F., Newman, L., Sebra, R., Merad, M., Sampson, H. A., Losic, B., & Berin, M. C. (2018). Single-cell profiling of peanut-responsive T cells in patients with peanut allergy reveals heterogeneous effector T _H 2 subsets Journal of Allergy and Clinical Immunology, 141(6), 2107-2120. https://doi.org/10.1016/j.jaci.2017.11.060

@article{5c4d38fb4b0a4245abac5cd4d2c870b3,

title = " Single-cell profiling of peanut-responsive T cells in patients with peanut allergy reveals heterogeneous effector T H 2 subsets ",

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 H 2 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 H 2 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 H 2 cells producing T H 2-associated cytokines with functions beyond IgE class-switching in patients with PA. A multifunctional T H 2 response was more evident than a Treg cell deficit among peanut-responsive T cells.",

keywords = "Food allergy, T 2, peanut allergy, regulatory T, tolerance",

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

note = "Publisher Copyright: {\textcopyright} 2018 American Academy of Allergy, Asthma & Immunology",

year = "2018",

month = jun,

doi = "10.1016/j.jaci.2017.11.060",

language = "English",

volume = "141",

pages = "2107--2120",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Mosby Inc.",

number = "6",

}

Chiang, D, Chen, X, Jones, SM, Wood, RA, Sicherer, SH, Burks, AW, Leung, DYM, Agashe, C, Grishin, A, Dawson, P, Davidson, WF, Newman, L, Sebra, R, Merad, M, Sampson, HA , Losic, B & Berin, MC 2018, ' Single-cell profiling of peanut-responsive T cells in patients with peanut allergy reveals heterogeneous effector T _H 2 subsets ', Journal of Allergy and Clinical Immunology, vol. 141, no. 6, pp. 2107-2120. https://doi.org/10.1016/j.jaci.2017.11.060

Single-cell profiling of peanut-responsive T cells in patients with peanut allergy reveals heterogeneous effector T _H 2 subsets . / Chiang, David; Chen, Xintong; Jones, Stacie M. et al.
In: Journal of Allergy and Clinical Immunology, Vol. 141, No. 6, 06.2018, p. 2107-2120.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Single-cell profiling of peanut-responsive T cells in patients with peanut allergy reveals heterogeneous effector T H 2 subsets

AU - Chiang, David

AU - Chen, Xintong

AU - Jones, Stacie M.

AU - Wood, Robert A.

AU - Sicherer, Scott H.

AU - Burks, A. Wesley

AU - Leung, Donald Y.M.

AU - Agashe, Charuta

AU - Grishin, Alexander

AU - Dawson, Peter

AU - Davidson, Wendy F.

AU - Newman, Leah

AU - Sebra, Robert

AU - Merad, Miriam

AU - Sampson, Hugh A.

AU - Losic, Bojan

AU - Berin, M. Cecilia

PY - 2018/6

Y1 - 2018/6

N2 - 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 H 2 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 H 2 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 H 2 cells producing T H 2-associated cytokines with functions beyond IgE class-switching in patients with PA. A multifunctional T H 2 response was more evident than a Treg cell deficit among peanut-responsive T cells.

AB - 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 H 2 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 H 2 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 H 2 cells producing T H 2-associated cytokines with functions beyond IgE class-switching in patients with PA. A multifunctional T H 2 response was more evident than a Treg cell deficit among peanut-responsive T cells.

KW - Food allergy

KW - T 2

KW - peanut allergy

KW - regulatory T

KW - tolerance

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U2 - 10.1016/j.jaci.2017.11.060

DO - 10.1016/j.jaci.2017.11.060

M3 - Article

C2 - 29408715

AN - SCOPUS:85042202801

SN - 0091-6749

VL - 141

SP - 2107

EP - 2120

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 6

ER -

Chiang D, Chen X, Jones SM, Wood RA, Sicherer SH, Burks AW et al. Single-cell profiling of peanut-responsive T cells in patients with peanut allergy reveals heterogeneous effector T _H 2 subsets Journal of Allergy and Clinical Immunology. 2018 Jun;141(6):2107-2120. 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 H 2 subsets

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Single-cell profiling of peanut-responsive T cells in patients with peanut allergy reveals heterogeneous effector T _H 2 subsets