Rhinitis, sinusitis, and upper airway disease
Rhinovirus has the unique ability to directly activate human T cells in vitro

https://doi.org/10.1016/j.jaci.2012.11.041Get rights and content

Background

Rhinovirus infection is a leading cause of exacerbation of airway diseases. We hypothesize that airway viruses activate inflammatory cells, inducing airway dysfunction. We have previously shown that airway viruses can induce eosinophil degranulation when cocultured with T cells and monocyte-derived dendritic cells (moDCs). These findings suggested that antigen presentation was important for T-cell activation.

Objective

Given the clinical importance of rhinovirus, we sought to determine whether it had any unique abilities to activate inflammatory cells compared with another common virus, such as respiratory syncytial virus (RSV).

Methods

We cocultured combinations of human leukocytes (T cells, moDCs, and eosinophils) with each virus. Using assays of BrdU incorporation, flow cytometry, and ELISA, we measured T-cell activation, rhinovirus expression, T-cell death, and eosinophil cysteinyl leukotriene release.

Results

In contrast to RSV, rhinovirus induced T-cell activation without the involvement of moDCs. Without moDCs, rhinovirus induced T-cell proliferation of both CD4 and CD8+ cells, cytokine production, and ultimately, eosinophil stimulation. Although chloroquine inhibited RSV-induced activation of T cells through moDCs, rhinovirus was not inhibited; UV inactivation did block the rhinovirus effect. We also found that T cells could be infected by rhinovirus in vitro and within human nasal explant tissue. Although Toll-like receptors did not appear to be involved in T-cell activation, antagonists of Jun N-terminal kinase and nuclear factor κB did inhibit T-cell responses to rhinovirus.

Conclusion

Rhinovirus has the unique ability to bypass antigen presentation and directly infect and activate human T cells. This could explain the strong association of rhinovirus with exacerbation of airway diseases.

Section snippets

Reagents

Cells were grown in RPMI 1640 with HEPES, 10% FBS, 2 mmol/L glutamine, and nonessential amino acids (Invitrogen, Carlsbad, Calif). LPS, Pam3CSK4, polyinosine-polycytidylic acid (poly[I:C]), and R-848 were from InvivoGen (San Diego, Calif). Fluorophore-labeled antibodies were from BD Biosciences (San Jose, Calif). RV-16 VP2 mAb (R16-VP2) was a kind gift from Dr James Gern, University of Wisconsin.18 See the Methods section in this article's Online Repository at www.jacionline.org for complete

Rhinovirus-induced T-cell proliferation does not depend on MHC-II–restricted antigen presentation

Our previous experiments with RSV and PIV indicated antigen-presenting cells (APCs) were a requisite for T-cell activation. We tested whether APCs were also required for rhinovirus-induced T-cell activation. First, we analyzed the role of MHC-II–restricted antigen presentation in rhinovirus-induced T-cell proliferation. Chloroquine inhibits MHC-II antigen presentation, hampering antigen processing and loading onto MHC-II molecules.22, 23, 24, 25 moDCs were exposed to RSV or rhinovirus, with or

Discussion

To understand the immune cell interactions that take place in the airways of patients with allergic asthma encountering viral infections, we developed an in vitro coculture model using autologous moDCs and T lymphocytes with eosinophils.8 In our study we found novel attributes of rhinovirus versus another common airway virus, which could explain, at least in part, the reason why rhinovirus is so adept at inducing inflammatory reactions.

For the first time, we provide evidence that rhinovirus has

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    Supported by the Canadian Institutes of Health Research. D.J.A. was an Alberta Heritage Clinical Investigator. R.I. received funding from CONACyT-Mexico. D.P. holds a Canada Research Chair in Inflammatory Airway Diseases.

    Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

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