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Expansion of the CD4+ effector T-cell repertoire characterizes peanut-allergic patients with heightened clinical sensitivity - 05/01/20

Doi : 10.1016/j.jaci.2019.09.033 
Bert Ruiter, PhD a, b, , Neal P. Smith, MS a, Brinda Monian, PhD c, Ang A. Tu, BS c, Elizabeth Fleming, BS a, Yamini V. Virkud, MD, MPH a, b, d, Sarita U. Patil, MD a, b, d, Charles A. Whittaker, PhD c, e, J. Christopher Love, PhD c, Wayne G. Shreffler, MD, PhD a, b, d
a Center for Immunology & Inflammatory Diseases, Massachusetts General Hospital, Boston, Mass 
b Harvard Medical School, Boston, Mass 
c Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Mass 
d Food Allergy Center, Massachusetts General Hospital, Boston, Mass 
e The Barbara K. Ostrom (1978) Bioinformatics and Computing Facility in the Swanson Biotechnology Center, Massachusetts Institute of Technology, Cambridge, Mass 

Corresponding author: Bert Ruiter, PhD, Center for Immunology & Inflammatory Diseases, Massachusetts General Hospital, Rm 8.409, 149 13th St, Boston, MA 02129.Center for Immunology & Inflammatory DiseasesMassachusetts General HospitalRm 8.409149 13th StBostonMA02129

Abstract

Background

Individuals with peanut allergy range in clinical sensitivity: some can consume grams of peanut before experiencing any symptoms, whereas others suffer systemic reactions to 10 mg or less. Current diagnostic testing only partially predicts this clinical heterogeneity.

Objective

We sought to identify characteristics of the peanut-specific CD4+ T-cell response in peanut-allergic patients that correlate with high clinical sensitivity.

Methods

We studied the T-cell receptor β-chain (TCRβ) usage and phenotypes of peanut-activated, CD154+ CD4+ memory T cells using fluorescence-activated cell sorting, TCRβ sequencing, and RNA-Seq, in reactive and hyporeactive patients who were stratified by clinical sensitivity.

Results

TCRβ analysis of the CD154+ and CD154 fractions revealed more than 6000 complementarity determining region 3 sequences and motifs that were significantly enriched in the activated cells and 17% of the sequences were shared between peanut-allergic individuals, suggesting strong convergent selection of peanut-specific clones. These clones were more numerous among the reactive patients, and this expansion was identified within effector, but not regulatory T-cell populations. The transcriptional profile of CD154+ T cells in the reactive group skewed toward a polarized TH2 effector phenotype, and expression of TH2 cytokines strongly correlated with peanut-specific IgE levels. There were, however, also non–TH2-related differences in phenotype. Furthermore, the ratio of peanut-specific clones in the effector versus regulatory T-cell compartment, which distinguished the clinical groups, was independent of specific IgE concentration.

Conclusions

Expansion of the peanut-specific effector T-cell repertoire is correlated with clinical sensitivity, and this observation may be useful to inform our assessment of disease phenotype and to monitor disease longitudinally.

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Graphical abstract




Le texte complet de cet article est disponible en PDF.

Key words : Peanut allergy, food allergy, clinical sensitivity, CD4+ T cell, effector T cell, regulatory T cell, TH2, CD154, TCRβ sequencing, RNA-Seq

Abbreviations used : CDR3, CDR3s, CFSE, DBPCFC, OIT, ps-CDR3s, ps-Teff, ps-Treg, TCRβ, Teff, Treg


Plan


 This work was supported by the National Institutes of Health/National Institute of Allergy and Infectious Diseases (grant no. U19AI095261 to W.G.S. and Andrew D. Luster, grant no. K23AI130408 to Y.V.V., and grant no. K23AI121491 to S.U.P.), Sanofi US, the Food Allergy Science Initiative, and institutional funds from Massachusetts General Hospital.
 Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interests.


© 2019  American Academy of Allergy, Asthma & Immunology. Publié par Elsevier Masson SAS. Tous droits réservés.
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Vol 145 - N° 1

P. 270-282 - janvier 2020 Retour au numéro
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