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

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 T_H2 effector phenotype, and expression of T_H2 cytokines strongly correlated with peanut-specific IgE levels. There were, however, also non-T_H2-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.

Keywords: CD154; CD4(+) T cell; Peanut allergy; RNA-Seq; T(H)2; TCRβ sequencing; clinical sensitivity; effector T cell; food allergy; regulatory T cell.