Targeting allergen to FcγRI reveals a novel TH2 regulatory pathway linked to thymic stromal lymphopoietin receptor

Kathryn E. Hulse, Amanda J. Reefer, Victor H. Engelhard, James T. Patrie, Steven F. Ziegler, Martin D. Chapman, Judith A. Woodfolk*

*Corresponding author for this work

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Background: The molecule H22-Fel d 1, which targets cat allergen to FcγRI 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 TH2-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 TH2 responses irrespective of atopic status; however, DCs coprimed with TSLP and H22-Fel d 1 selectively and synergistically amplified TH2 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 FcγRI-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 TH2 responses. Conclusion: Discovery of a novel TH2 regulatory pathway linking FcγRI signaling to TSLP receptor upregulation and consequent TSLP-mediated effects questions the validity of receptor-targeted allergen vaccines.

Original languageEnglish (US)
JournalJournal of Allergy and Clinical Immunology
Volume125
Issue number1-3
DOIs
StatePublished - Jan 1 2010

Fingerprint

Allergens
Dendritic Cells
Cats
T-Lymphocytes
OX40 Ligand
Flow Cytometry
Hypersensitivity
thymic stromal lymphopoietin
Up-Regulation
Cytokines
1-Phosphatidylinositol 4-Kinase
src-Family Kinases
Fc Receptors
Atopic Dermatitis
Monocytes
Vaccines

Keywords

  • FcγRI
  • H22-Fel d 1
  • atopic dermatitis
  • blood dendritic cells
  • monocyte-derived dendritic cells
  • thymic stromal lymphopoietin
  • thymic stromal lymphopoietin receptor

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Hulse, Kathryn E. ; Reefer, Amanda J. ; Engelhard, Victor H. ; Patrie, James T. ; Ziegler, Steven F. ; Chapman, Martin D. ; Woodfolk, Judith A. / Targeting allergen to FcγRI reveals a novel TH2 regulatory pathway linked to thymic stromal lymphopoietin receptor. In: Journal of Allergy and Clinical Immunology. 2010 ; Vol. 125, No. 1-3.
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abstract = "Background: The molecule H22-Fel d 1, which targets cat allergen to FcγRI 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 TH2-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 TH2 responses irrespective of atopic status; however, DCs coprimed with TSLP and H22-Fel d 1 selectively and synergistically amplified TH2 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 FcγRI-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 TH2 responses. Conclusion: Discovery of a novel TH2 regulatory pathway linking FcγRI signaling to TSLP receptor upregulation and consequent TSLP-mediated effects questions the validity of receptor-targeted allergen vaccines.",
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author = "Hulse, {Kathryn E.} and Reefer, {Amanda J.} and Engelhard, {Victor H.} and Patrie, {James T.} and Ziegler, {Steven F.} and Chapman, {Martin D.} and Woodfolk, {Judith A.}",
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Targeting allergen to FcγRI reveals a novel TH2 regulatory pathway linked to thymic stromal lymphopoietin receptor. / Hulse, Kathryn E.; Reefer, Amanda J.; Engelhard, Victor H.; Patrie, James T.; Ziegler, Steven F.; Chapman, Martin D.; Woodfolk, Judith A.

In: Journal of Allergy and Clinical Immunology, Vol. 125, No. 1-3, 01.01.2010.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Targeting allergen to FcγRI reveals a novel TH2 regulatory pathway linked to thymic stromal lymphopoietin receptor

AU - Hulse, Kathryn E.

AU - Reefer, Amanda J.

AU - Engelhard, Victor H.

AU - Patrie, James T.

AU - Ziegler, Steven F.

AU - Chapman, Martin D.

AU - Woodfolk, Judith A.

PY - 2010/1/1

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N2 - Background: The molecule H22-Fel d 1, which targets cat allergen to FcγRI 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 TH2-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 TH2 responses irrespective of atopic status; however, DCs coprimed with TSLP and H22-Fel d 1 selectively and synergistically amplified TH2 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 FcγRI-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 TH2 responses. Conclusion: Discovery of a novel TH2 regulatory pathway linking FcγRI signaling to TSLP receptor upregulation and consequent TSLP-mediated effects questions the validity of receptor-targeted allergen vaccines.

AB - Background: The molecule H22-Fel d 1, which targets cat allergen to FcγRI 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 TH2-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 TH2 responses irrespective of atopic status; however, DCs coprimed with TSLP and H22-Fel d 1 selectively and synergistically amplified TH2 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 FcγRI-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 TH2 responses. Conclusion: Discovery of a novel TH2 regulatory pathway linking FcγRI signaling to TSLP receptor upregulation and consequent TSLP-mediated effects questions the validity of receptor-targeted allergen vaccines.

KW - FcγRI

KW - H22-Fel d 1

KW - atopic dermatitis

KW - blood dendritic cells

KW - monocyte-derived dendritic cells

KW - thymic stromal lymphopoietin

KW - thymic stromal lymphopoietin receptor

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