Allergen recognition by specific effector Th2 cells enables IL‐2‐dependent activation of regulatory T‐cell responses in humans

Type 2 allergen‐specific T cells are essential for the induction and maintenance of allergies to foods, and Tregs specific for these allergens are assumed to be involved in their resolution. However, it has not been convincingly demonstrated whether allergen‐specific Treg responses are responsible for the generation of oral tolerance in humans. We observed that sustained food allergen exposure in the form of oral immunotherapy resulted in increased frequency of Tregs only in individuals with lasting clinical tolerance. We sought to identify regulatory components of the CD4+ T‐cell response to food allergens by studying their functional activation over time in vitro and in vivo. Two subsets of Tregs expressing CD137 or CD25/OX40 were identified with a delayed kinetics of activation compared with clonally enriched pathogenic effector Th2 cells. Treg activation was dependent on IL‐2 derived from effector T cells. In vivo exposure to peanut in the form of an oral food challenge of allergic subjects induced a delayed and persistent activation of Tregs after initiation of the allergen‐specific Th2 response. The novel finding of our work is that a sustained wave of Treg activation is induced by the release of IL‐2 from Th2 effector cells, with the implication that therapeutic administration of IL‐2 could improve current OIT approaches. Initiation of allergen‐specific Th2 cell responses generates an IL‐2‐mediated activation of Tregs. IL‐2‐activated T cells exert an immunosuppressive effect on effector T cells. In vivo exposure to peanut induces a delayed and persistent activation of Tregs.Abbreviations: ICOS, inducible T‐cell co‐stimulator; IL, interleukin; LAP, latency‐associated peptide; OX40, TNF receptor superfamily member 4; PD1, programmed cell death protein 1; Th, T helper cell; Treg, regulatory T cell.