The critical role of memory CD4+ T cells in the inaugural generation of IgE

Abstract

The global prevalence of food allergies is estimated at 10%, and approximately 80% of food allergies are lifelong. Food allergies are primarily mediated by allergen-specific IgE, which drives allergic reactions and is the hallmark of allergic sensitization. However, the initial generation of IgE is clinically silent and many patients present to the emergency department or clinic upon their first allergic reaction, whereupon they are already sensitized. This feature of allergic disease renders it difficult to study the incipient cellular events leading to inaugural IgE generation in humans, which may be important for generating lifelong allergic memory. Using a mouse model of intragastric sensitization, we demonstrated that a single priming exposure to allergen alongside cholera toxin (CT) generates allergen-specific memory CD4+ T cells which reside across multiple tissue sites, yet fails to induce B cell activation, antibody production, or clinical reactivity. These allergen-specific CD4+ T cells resemble Teff cells but remain undifferentiated to typical allergy-associated T helper cell lineages, such as Th2 and Tfh cells, and IL-4Rα-mediated signaling is dispensable for their generation. Up to 14 months after their initial generation, primed memory CD4+ T cells potently expanded and displayed plasticity upon allergen re-exposures. They differentiated into IL-4-transcribing Tfh cells and drove de novo IgE class-switching in naïve B cells, leading to allergen-specific IgE generation and clinical reactivity. This recall response was dependent on IL-4 signaling and CD40/CD40L interactions and occurred across multiple tissue sites independent of S1PR-mediated cell migration, suggesting the potency of memory CD4+ T cells in maintaining allergic memory. Altogether, our findings suggest that these plastic memory CD4+ T cells are capable of independently perpetuating allergic disease. Our work positions memory CD4+ T cells as a potentially crucial therapeutic target, which may aid in the design of disease-modifying therapeutics which induce long-term remission of food allergy in patients.