Rhinovirus infection interferes with induction of tolerance to aeroantigens through OX40 ligand, thymic stromal lymphopoietin, and IL-33

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:137

Article

Mehta, Amit K.¹  Duan, Wei¹  Doerner, Astrid M.^2,3  Traves, Suzanne L.⁴  Broide, David H.³  Proud, David⁴  Zuraw, Bruce L.^2,3  Croft, Michael¹ 

[1] La Jolla Inst Allergy & Immunol, Div Immune Regulat, La Jolla, CA 92037 USA

[2] Univ Calif San Diego, Vet Med Res Fdn, La Jolla, CA 92093 USA

[3] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA

[4] Univ Calgary, Fac Med, Airway Inflammat Res Grp, Snyder Inst Chron Dis,Dept Physiol & Pharmacol, Calgary, AB T2N 1N4, Canada

关键词: Asthma;    epithelial cell;    OX40 ligand;    RV1B;    RV16;    thymic stromal lymphopoietin;    peripherally induced regulatory T cell;   

DOI  :  10.1016/j.jaci.2015.05.007

来源: Elsevier

【 摘 要 】

Background: Rhinovirus infection at an early age has been associated with development of asthma, but how rhinovirus influences the immune response is not clear. Objective: Tolerance to inhaled antigen is mediated through induction of regulatory T (Treg) cells, and we examined whether rhinovirus infection of the respiratory tract can block airway tolerance by modulating Treg cells. Methods: The immune response to intranasal ovalbumin in mice was assessed with concomitant infection with RV1B, and the factors induced in vivo were compared with those made by human lung epithelial cells infected in vitro with RV16. Results: RV1B infection of mice abrogated tolerance induced by inhalation of soluble ovalbumin, suppressing the normal generation of forkhead box protein 3-positive Treg cells while promoting TH2 cells. Furthermore, RV1B infection led to susceptibility to asthmatic lung disease when mice subsequently re-encountered aeroantigen. RV1B promoted early in vivo expression of the TNF family protein OX40 ligand on lung dendritic cells that was dependent on the innate cytokine thymic stromal lymphopoietin (TSLP) and also induced another innate cytokine, IL-33. Inhibiting each of these pathways allowed the natural development of Treg cells while minimizing TH2 differentiation and restored tolerance in the face of RV1B infection. In accordance, RV16 infection of human lung epithelial cells upregulated TSLP and IL-33 expression. Conclusions: These results suggest that infection of the respiratory epithelium with rhinovirus can antagonize tolerance to inhaled antigen through combined induction of TSLP, IL-33, and OX40 ligand and that this can lead to susceptibility to asthmatic lung inflammation.

【 授权许可】

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