Signaling through FcRγ-associated receptors on dendritic cells drives IL-33-dependent TH2-type responses

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:134

Article

Tjota, Melissa Y.^1,2  Hrusch, Cara L.³  Blaine, Kelly M.³  Williams, Jesse W.⁴  Barrett, Nora A.⁵  Sperling, Anne I.^1,3 

[1] Univ Chicago, Comm Immunol, Chicago, IL 60637 USA

[2] Univ Chicago, Med Scientist Training Program, Chicago, IL 60637 USA

[3] Univ Chicago, Dept Med, Sect Pulm & Crit Care Med, Chicago, IL 60637 USA

[4] Univ Chicago, Comm Mol Pathogenesis & Mol Med, Chicago, IL 60637 USA

[5] Harvard Univ, Sch Med, Dept Med, Div Rheumatol Immunol & Allergy, Boston, MA USA

关键词: Dendritic cells;    immune complexes;    house dust mite;    FcR gamma;    T(H)2;    allergic airway inflammation;    lungs;   

DOI  :  10.1016/j.jaci.2014.06.013

来源: Elsevier

【 摘 要 】

Background: Although allergic sensitization can be generated against various allergens, it is unknown how such a diversity of antigens is able to promote T(H)2-mediated inflammation leading to atopy. Our previous studies demonstrated that allergen-specific IgG immune complexes (ICs) and house dust mite (HDM) extract both induced dendritic cells (DCs) to drive T(H)2-mediated inflammation, but the mechanism by which these diverse stimuli produce similar responses is unknown. Objective: We sought to identify the DC signaling pathways used by T(H)2 stimuli to promote T(H)2-mediated inflammation. Methods: C57BL/6, Fc gamma RIII-/-, FcR gamma(-/-), and ST2(-/-) mice were sensitized and challenged with HDM, and inflammation was assessed based on results of flow cytometry and histology and cytokine production. Bone marrow-derived DCs from these strains were used in signaling and adoptive transfer experiments. Results: Our findings indicate that 2 distinct T(H)2 stimuli, ICs and HDM, use the FcR gamma-associated receptors Fc gamma RIII and Dectin-2, respectively, to promote T(H)2-mediated lung inflammation. In this study we demonstrate that both ICs and HDM induce expression of IL-33, a critical mediator in asthma pathogenesis and the differentiation of T(H)2 cells, in DCs. Upregulation of IL-33 in DCs is dependent on FcR gamma, Toll-like receptor 4, and phosphoinositide 3-kinase. Exogenous IL-33 is sufficient to restore the development of T(H)2 responses in FcR gamma-deficient mice. Finally, adoptive transfer of allergen-pulsed FcR gamma(+/-) bone-marrow derived DCs restores the development of T(H)2-type inflammation in FcR gamma-deficient mice, demonstrating the necessity of this signaling pathway in DCs for allergen-induced inflammation. Conclusion: These data identify a mechanism whereby T(H)2 stimuli signal through FcR gamma-associated receptors on DCs to upregulate IL-33 production and induce T(H)2-mediated allergic airway inflammation.

【 授权许可】

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