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Peanut oral immunotherapy differentially suppresses clonally distinct subsets of T helper cells
Brinda Monian, Ang A. Tu, Bert Ruiter, Duncan M. Morgan, Patrick M. Petrossian, Neal P. Smith, Todd M. Gierahn, Julia H. Ginder, Wayne G. Shreffler, J. Christopher Love
Brinda Monian, Ang A. Tu, Bert Ruiter, Duncan M. Morgan, Patrick M. Petrossian, Neal P. Smith, Todd M. Gierahn, Julia H. Ginder, Wayne G. Shreffler, J. Christopher Love
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Research Article Immunology

Peanut oral immunotherapy differentially suppresses clonally distinct subsets of T helper cells

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Abstract

Food allergy affects an estimated 8% of children in the United States. Oral immunotherapy (OIT) is a recently approved treatment, with outcomes ranging from sustained tolerance to food allergens to no apparent benefit. The immunological underpinnings that influence clinical outcomes of OIT remain largely unresolved. Using single-cell RNA-Seq and paired T cell receptor α/β (TCRα/β) sequencing, we assessed the transcriptomes of CD154+ and CD137+ peanut-reactive T helper (Th) cells from 12 patients with peanut allergy longitudinally throughout OIT. We observed expanded populations of cells expressing Th1, Th2, and Th17 signatures that further separated into 6 clonally distinct subsets. Four of these subsets demonstrated a convergence of TCR sequences, suggesting antigen-driven T cell fates. Over the course of OIT, we observed suppression of Th2 and Th1 gene signatures in effector clonotypes but not T follicular helper–like (Tfh-like) clonotypes. Positive outcomes were associated with stronger suppression of Th2 signatures in Th2A-like cells, while treatment failure was associated with the expression of baseline inflammatory gene signatures that were present in Th1 and Th17 cell populations and unmodulated by OIT. These results demonstrate that differential clinical responses to OIT are associated with both preexisting characteristics of peanut-reactive CD4+ T cells and suppression of a subset of Th2 cells.

Authors

Brinda Monian, Ang A. Tu, Bert Ruiter, Duncan M. Morgan, Patrick M. Petrossian, Neal P. Smith, Todd M. Gierahn, Julia H. Ginder, Wayne G. Shreffler, J. Christopher Love

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Figure 5

Th1 and Th2 effector, but not Tfh-like, subsets are suppressed by OIT.

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Th1 and Th2 effector, but not Tfh-like, subsets are suppressed by OIT.
(...
(A) Mean Th2, Th1 and Th17 gene module expression over time within Th2, Th1, and Th17 clones (see Methods), respectively, in each treatment group patient at each time point. (B) Fractional expression of Th2, Th1, and Th17 modules within clonotypes of Th subtypes over time. Fractional clonal expression is defined as the proportion of cells within each clonotype expressing their respective module (see Methods). Each data point represents the cells of an individual expanded clonotype from 1 patient at 1 time point. Patients in the placebo group were excluded. (C) Degree of suppression in Th2A-like clones by clinical group. The ratio of mean Th2 module expression in Th2A-like clones from each patient was calculated between buildup and maintenance. Spearman’s rho = 0.74; *P < 0.05. n = 9. Spearman’s test was performed to determine the correlation between ratio and outcome within the treatment group (assigning 2 for tolerance, 1 for partial tolerance, and 0 for treatment failure to represent the ordinal relationship between treatment groups). (D) PC1 score for CD154+ cells by outcome. PCA was performed using the 50 gene modules as features and all CD154+ cells at baseline as the input data (see Methods). Each data point represents the mean PC1 score for all CD154+ cells from a single patient at a single time point. Black-outlined data points represent the baseline time point. (E) Top 5 gene module loadings in PC1. Bar heights represent the magnitude of each contribution to PC1. (See Supplemental Figures 4 and 5 for further details on each gene module.) *P < 0.05 (adjusted), **P < 0.005 (adjusted), and ****P < 0.0005 (adjusted), by paired (A) or unpaired (B and D) Wilcoxon rank-sum test.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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