Targeting allergen to Fc gamma RI reveals a novel T sub(H2 regulatory pathway linked to thymic stromal lymphopoietin receptor)

We sought to investigate whether the T-cell response induced by H22-Fel d 1 is altered in the presence of the T sub(H2-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 1 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 1 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) sub(H)2 responses irrespective of atopic status; however, DCs coprimed with TSLP and H22-Fel d 1 selectively and synergistically amplified T sub(H2 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) sub(H)2 responses. Conclusion: Discovery of a novel T sub(H2 regulatory pathway linking Fc gamma RI signaling to TSLP receptor upregulation and consequent TSLP-mediated effects questions the validity of receptor-targeted allergen vaccines.)