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

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 3

Gene modules for Th function are associated with clonal expansion and expression in activated cells.

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Gene modules for Th function are associated with clonal expansion and ex...
(A) Clonal size of TCRα sequence (left) or TCRβ sequence (right) for all cells with paired TCR recovery, overlaid onto UMAP coordinates. Clonal size is defined as the number of cells sharing a TCR sequence. (B) Diversity (normalized Shannon index) of TCRβ repertoires of each sorted subset. Each data point represents the repertoire for 1 patient at 1 time point (CD137+: n = 41; CD154+: n = 44; CD154–CD137–: n = 23). (C) Distribution of TCRβ clonal sizes, within each sorted subset. Cells within each sorted subset were downsampled to equal numbers before clonal sizes were calculated. (D) Percentage of TCRβ sequences shared between time points and sorted subsets. The percentage shared is defined as the number of unique TCRβ sequences detected in both conditions, divided by the geometric mean of the number of unique TCRβ sequences in each of the 2 conditions. Sequences from all patients with samples in all 3 conditions (n = 6 patients) were pooled. (E) Mean clonal size and fold change in mean module scores (compared with module-expressing CD154–CD137– cells) in CD154+ cells expressing each gene module. Each data point represents a single gene module. Cells were classified as “expressing” each module or not, relative to background expression (see Methods). Clonal size was calculated with respect to all cells in the data set. ****P < 0.0001 (adjusted), by unpaired Wilcoxon rank-sum test. Data represent combined data from all patients at all time points (A–C and E).