Divergent Target Specificity of Foxp3+ Regulatory T Cells and Th2 Effector Cells in Patients Allergic to A. fumigatus

Foxp3+ regulatory T cells (Treg) are thought to play a central role in maintaining tolerance against harmless antigens at mucosal sites. However, which antigens are actually recognized by Treg in particular in humans is so far not known. We established a highly sensitive enrichment system to detect antigen-specific conventional T cells (Tcon) and Treg, based on antigen-induced CD154 (CD40L) versus CD137 (4-1BB) expression. We show that the airborne fungus A. fumigatus induces a dominant population of CD4+CD25+CD127-Foxp3+Helios+ Treg in peripheral blood of healthy donors, with demethylated TSDR and potent in vitro suppressive activity. Intriguingly, the strong Treg response contrasts with minimal memory Tcon. This Treg dominance is abrogated in subjects allergic to A. fumigatus, due to a massive expansion of conventional Th2-type memory cells. However, in allergic donors, Treg are still abundant but surprisingly have non-overlapping protein targets with Th2 cells.Our data identify A. fumigatus as a major target of human Treg and provide direct evidence that antigen-specific Treg are potent suppressors of allergy development. Furthermore we provide an explanation how allergen-specific Th2 responses can escape Treg control due to selective targeting of A. fumigatus proteins not protected by a specific Treg response.