Single-cell profiling of peanut-responsive T cells in patients with peanut allergy reveals heterogeneous effector TH2 subsets - 06/06/18
, M. Cecilia Berin, PhD a, ⁎∗ 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 TH2 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 TH2 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 TH2 cells producing TH2-associated cytokines with functions beyond IgE class-switching in patients with PA. A multifunctional TH2 response was more evident than a Treg cell deficit among peanut-responsive T cells.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : Food allergy, peanut allergy, TH2, regulatory T, tolerance
Abbreviations used : CoFAR, CRTH2, CSF2, DEG, FoxP3, HC, HT, MSSM, PA, peTH2, RNA-seq, TCR, Treg
Plan
| Supported by U24AI118644 (to M.C.B. and M.M.) and the David and Julia Koch Research Program in Food Allergy Therapeutics (to H.A.S.). Facilities were supported by an NCI P30 Cancer Center Support Grant (P30 CA196521). MSSM PA cohort samples were kindly supplied by the Food Allergy Resource Initiative, which is supported by funding from Food Allergy Research & Education and maintained at the Elliot and Roslyn Jaffe Food Allergy Institute, Icahn School of Medicine at Mount Sinai. The clinical study (CoFAR6) providing samples for this study is registered with ClinicalTrials.gov with ID NCT01904604 and is supported by National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID) grants U19AI066738 and U01AI066560. The project was also supported by NIH/National Center for Advancing Translational Sciences (NCATS) grant nos. UL1 TR0001082 (Colorado), UL1 TR000067 (Mount Sinai), UL1 TR000039 (Arkansas), UL1 TR000083 (North Carolina), and UL1 TR000424 (Johns Hopkins) from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH). Support for this trial was also provided by DBV Technologies (Montrouge, France) through funds provided to the Consortium of Food Allergy Research. |
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| Disclosure of potential conflict of interest: S. M. Jones' institution received a grant from DBV Technologies for this work and grants from DBV Technologies, Aimmune, and Astellas for other works and personally received fees for participation in review activities for this work from DBV Technologies and holds a board membership from Aimmune Therapeutics and Food Allergy Research & Education. R. A. Wood's institution received a grant from the National Institutes of Health (NIH) for this work and grants from the NIH, DBV, Astellas, HAL-Allergy, and Aimmune for other works; is employed by Johns Hopkins University; and received royalties from UpToDate. S. H. Sicherer's institute received a grant from the National Institute of Allergy and Infectious Diseases (NIAID) for this work and other works; is employed by the Icahn School of Medicine at Mount Sinai; and served as journal editor for the American Academy of Allergy, Asthma & Immunology. A. W. Burks received personal fees from the NIH HAI Study Section, the NIH AITC Review Panel, Allertein, the American Society for Microbiology, Elsevier, Food Allergy Research & Education, and the World Allergy Organization; grants from Food Allergy Research & Education, the National Institutes of Health, and the Wallace Research Foundation; received consultancy fees from Adept Field Solutions, Aimmune Therapeutics, Astellas Pharma Global Development, Biomerica, Evelo Biosciences/Epiva Biosciences, First Manhattan, Genentech, GLG Research, Insys Therapeutics, Intrommune Therapeutics, PPD Development, LP, Regeneron Pharmaceuticals, Sanofi US Services, SRA International, Stallergenes, UKKO, and Valeant Pharmaceuticals North America; and is on the advisory board for Aimmune Therapeutics. D. Y. M. Leung is a consultant for Regeneron and Sanofi. A. Grishin's institution received a grant from the NIH/NIAID for this work, and he personally received consultancy fees from N-Fold. P. Dawson's institution received grants from the DAIT/NIAID/NIH for this work. R. Sebra is employed by Sema4, a Mount Sinai Venture, and his institution received grants from the NIH for other works. H. A. Sampson's institution received grant AI-44236 from the NIAID, AI-44236 from the Immune Tolerance Network, UM1-Al109565 (PI-Burks) from the Immune Tolerance Network, P30-ES023515 (PI-Wright) from the NIH/National Institute of Environmental Health Sciences (NIEHS) for this work and a grant from the NIAID for other works; received consultancy fees from Allertein Therapeutics, Hycor, and UCB; is employed by DBV Technologies; received royalties from UpToDate; and received stock options from DBV Technologies. M. C. Berin's institution received a grant from the NIAID for this work. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 141 - N° 6
P. 2107-2120 - juin 2018 Retour au numéro
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