Targeting allergen to Fc gamma RI reveals a novel T(H)2 regulatory pathway linked to thymic stromal lymphopoietin receptor

Background: The molecule H22-Fel d 1, which targets cat allergen to Fc gamma RI on dendritic cells (DCs), has the potential to treat cat allergy because of its T-cell modulatory properties. Objective: We sought to investigate whether the T-cell response induced by H22-Fel d I is altered in the presence of the T(H)2-promoting cytokine thymic stromal lymphopoietin (TSLP). Methods: Studies were performed in subjects with cat allergy with and without atopic dermatitis. Monocyte-derived DCs were primed with H22-Fel d I in the presence or absence of TSLP, and the resulting T-cell cytokine repertoire was analyzed by flow cytometry. The capacity for H22-Fel d I to modulate TSLP receptor expression on DCs was examined by flow cytometry in the presence or absence of inhibitors of Fc receptor signaling molecules. Results: Surprisingly, TSLP alone was a weak inducer of T(H)2 responses irrespective of atopic status; however, DCs coprimed with TSLP and H22-Fel d I selectively and synergistically amplified T(H)2 responses in highly atopic subjects. This effect was OX40 ligand independent, pointing to an unconventional TSLP-mediated pathway. Expression of TSLP receptor was upregulated on atopic DCs primed with H22-Fel d 1 through a pathway regulated by Fc gamma RI-associated signaling components, including src-related tyrosine kinases and Syk, as well as the downstream molecule phosphoinositide 3-kinase. Inhibition of TSLP receptor upregulation triggered by H22-Fel d 1 blocked TSLP-mediated T(H)2 responses. Conclusion: Discovery of a novel T(H)2 regulatory pathway linking Fc gamma RI signaling to TSLP receptor upregulation and consequent TSLP-mediated effects questions the validity of receptor-targeted allergen vaccines. (J Allergy Clin Immunol 2010;125:247-56.)