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

Abstract

Background Rhinovirus (RV) infection during an early age has been associated with development of asthma, but how RV influences the immune response is not clear. Objective Tolerance to inhaled antigen is mediated via the induction of regulatory T cells (Treg), and we asked whether RV infection of the respiratory tract might block airway tolerance by modulating Treg cells. Methods The immune response to intranasal ovalbumin (OVA) in mice was assessed with concomitant infection with RV1B, and the factors induced in vivo were compared to factors made by human lung epithelial cells infected in vitro with RV16. Results RV1B infection of mice abrogated tolerance induced by inhalation of soluble OVA, suppressing the normal generation of Foxp3+ Treg cells while promoting Th2 cells. Furthermore, RV1B infection led to susceptibility to develop asthmatic lung disease when mice subsequently reencountered aeroantigen. RV1B promoted early in vivo expression of the TNF family protein, OX40L, 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 RV can antagonize tolerance to inhaled antigen through a combined induction of TSLP, IL-33 and OX40L, and this may lead to susceptibility to developing asthmatic lung inflammation.

IL-33 dysregulates regulatory T cells and impairs established immunologic tolerance in the lungs

“…8 Exposure to protease activities in allergens or infection with rhinovirus impairs development of these Treg cells by promoting expression of OX40L by DCs and by creating a lung environment rich in pro-inflammatory mediators, such as TSLP, IL-33, IL-1, IL-6, and TNF-α. 7, 8, 45 These findings suggest the importance of the balance between TGF-β and pro-inflammatory cytokines/molecules in the development of Treg cells in the lungs. Our findings in this study add to this knowledge by demonstrating that previously established Treg cells and immunological tolerance in the lungs were not sustained in the presence of an innate cytokine, IL-33.…”

Rhinovirus Infection of ORMDL3 Transgenic Mice Is Associated with Reduced Rhinovirus Viral Load and Airway Inflammation

“…RV1B was a generous gift of Dr. Michael Croft (La Jolla Inst for Allergy and Immunology, La Jolla, CA)(11). The RV1B was propagated in Ohio HeLa cells (ECACC, UK), at 33°C, in a humidified, 5% CO2 incubator as described (11).…”

Pathogenic CD4 + T cells in patients with asthma

“…The role of respiratory viruses, such as respiratory syncytial virus and HRV, in the development of early-onset wheeze is well established. 139 These viruses trigger many of the same innate cytokines as allergens, including TSLP and IL-33, 63,140,141 yet are potent inducers of T H 1 responses. HRV, the major cause of the common cold, induces acute wheezing episodes in allergic asthmatic patients.…”