Mixed Signals: T Cells as Architects of IgE Immunity

Abstract

Food allergen-specific IgE can cause significant pathology, yet the pathways that generate pathogenic, high-affinity IgE remain incompletely understood. Increasing evidence suggests that IgE responses arise from the integration of multiple, and sometimes opposing, T cell–derived cues. T follicular helper (Tfh) cells shape affinity maturation within germinal centers and likely coordinate class switching, while tissue-resident Th2 cells amplify local inflammation and potentially reinforce IgE production. Distinct Tfh subsets, characterized by differential production of IL-4 and IL-13, may further determine whether IgE responses remain low-affinity or mature into high-affinity antibodies capable of driving anaphylaxis. At the same time, regulatory populations—including regulatory T (Treg) cells and T follicular regulatory (Tfr) cells—impose restraints that can dampen or redirect humoral immunity. Early-life antigen exposure may tip this balance toward durable tolerance or toward progressive diversification of pathogenic IgE. Together, these mixed signals from helper, regulatory, and innate-like T cells likely determine the magnitude, affinity, and clinical impact of IgE responses. In this review, we explore how these intersecting pathways collectively regulate IgE immunity.