Targeting allergen to FcgammaRI 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 FcgammaRI 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 1 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 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(H)2 responses irrespective of atopic status; however, DCs coprimed with TSLP and H22-Fel d 1 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 FcgammaRI-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.


CONCLUSIONS
Discovery of a novel T(H)2 regulatory pathway linking FcgammaRI signaling to TSLP receptor upregulation and consequent TSLP-mediated effects questions the validity of receptor-targeted allergen vaccines.
Hulse
Kathryn E
KE
Asthma and Allergic Diseases Center, University of Virginia Health System, Charlottesville, VA 22908-1355, USA.
Reefer
Amanda J
AJ
Engelhard
Victor H
VH
Patrie
James T
JT
Ziegler
Steven F
SF
Chapman
Martin D
MD
Woodfolk
Judith A
JA
D000818:Animals; D017951:Antigen Presentation; D002415:Cats; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D003876:Dermatitis, Atopic / Q000276:immunology / Q000517:prevention & control; D005434:Flow Cytometry; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000276:immunology / Q000517:prevention & control; D018121:Receptors, Cytokine / Q000378:metabolism*; D017452:Receptors, IgG / Q000378:metabolism*; D015398:Signal Transduction; D018418:Th2 Cells / Q000276:immunology*; D015854:Up-Regulation; D000094632:Thymic Stromal Lymphopoietin
C498762:CRLF2 protein, human; D016207:Cytokines; C489017:FCGR1A protein, human; D006023:Glycoproteins; D018121:Receptors, Cytokine; D017452:Receptors, IgG; C059296:Fel d 1 protein, Felis domesticus; D000094632:Thymic Stromal Lymphopoietin