Wasp venom immunotherapy induces activation and homing of CD4 +CD25 + forkhead box protein 3–positive regulatory T cells controlling T H1 responses

Abstract

Despite a growing interest in CD4(+)CD25(+) forkhead box protein 3 (Foxp3)-positive regulatory T (Treg) cells, the fundamental parameters of the activation and homing of these cells during wasp venom immunotherapy (VIT) are largely unknown. We investigated longitudinally the phenotype and function of Treg cells in a well-characterized homogeneous group of patients with wasp venom allergy during VIT. In 30 patients peripheral Treg cells were ex vivo monitored for their activation status and homing capacities by means of flow cytometric analysis before and after 1 and 6 months of VIT. In addition, the in vitro suppressive activity of Treg cells, as well as cytokine secretion, in response to wasp venom was analyzed. One month after initiating VIT, the proportion of both CD4(+)CD25(+)Foxp3(+) and CD4(+)Foxp3(+) Treg cells significantly decreased in peripheral blood. Coexpression of the lymph node homing receptors CCR7/CD62L were induced in CD4(+)Foxp3(+)CD45RO(+) Treg cells, indicating recirculation of VIT-activated Treg cells in secondary lymphoid organs. In vivo imaging by means of color duplex ultrasonography of the axillary draining lymph nodes demonstrated a VIT-induced 4-fold augmentation in afferent arterial blood flow. Furthermore, increased activation markers (CD45RO and HLA-DR) of Treg cells correlated with effective in vitro suppression of wasp venom-driven T-cell proliferation. After 1 month of VIT, Treg cell depletion in vitro greatly enhanced wasp venom-induced IFN-γ secretion. Allergen exposure during VIT simultaneously induces the activation and selective homing of circulating Treg cells. Functionally, on the one hand, Treg cells balance the immune reaction toward tolerance, and on the other hand, they are involved in controlling overwhelming T(H)1 responses.