Article | Published:

Early infection with respiratory syncytial virus impairs regulatory T cell function and increases susceptibility to allergic asthma

Nature Medicine volume 18, pages 15251530 (2012) | Download Citation

Abstract

Immune tolerance is instituted early in life, during which time regulatory T (Treg) cells have an important role. Recurrent infections with respiratory syncytial virus (RSV) in early life increase the risk for asthma in adult life. Repeated infection of infant mice tolerized to ovalbumin (OVA) through their mother's milk with RSV induced allergic airway disease in response to OVA sensitization and challenge, including airway inflammation, hyper-reactivity and higher OVA-specific IgE, as compared to uninfected tolerized control mice. Virus infection induced GATA-3 expression and T helper type 2 (TH2) cytokine production in forkhead box P3 (FOXP3)+ Treg cells and compromised the suppressive function of pulmonary Treg cells in a manner that was dependent on interleukin-4 receptor α (IL-4Rα) expression in the host. Thus, by promoting a TH2-type inflammatory response in the lung, RSV induced a TH2-like effector phenotype in Treg cells and attenuated tolerance to an unrelated antigen (allergen). Our findings highlight a mechanism by which viral infection targets a host-protective mechanism in early life and increases susceptibility to allergic disease.

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Acknowledgements

We thank E. Shevach and G. Chattopadhyay (Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, US National Institutes of Health (NIH)) for providing spleens of OT-II × FOXP3-eGFP knock-in mice and J. Zhu (Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, NIH) for his efforts in identifying the source of these mice. DO11.10 transgenic mice were originally provided by K. Murphy (Washington University, St. Louis). This work was supported by NIH grants HL060207 and AI093116 (to P.R.), HL 077430 and AI048927 (to A.R.) and U19 AI095227 (to R.S.P.).

Author information

Author notes

    • Anupriya Khare
    •  & Timothy B Oriss

    These authors contributed equally to this work.

Affiliations

  1. Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

    • Nandini Krishnamoorthy
    • , Anupriya Khare
    • , Timothy B Oriss
    • , Mahesh Raundhal
    • , Christina Morse
    • , Manohar Yarlagadda
    • , Sally E Wenzel
    • , Anuradha Ray
    •  & Prabir Ray
  2. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

    • Mahesh Raundhal
    • , Anuradha Ray
    •  & Prabir Ray
  3. Department of Pediatrics, Emory University, Atlanta, Georgia, USA.

    • Martin L Moore
  4. Children's Healthcare of Atlanta, Atlanta, Georgia, USA.

    • Martin L Moore
  5. Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

    • R Stokes Peebles Jr

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Contributions

N.K. designed and performed experiments, analyzed data and wrote the manuscript. A.K. and T.B.O. performed cell sorting and analyzed flow cytometry data. M.R. performed qRT-PCR, C.M. performed lung function tests and assisted in the analysis of ELISPOT data, and M.Y. performed mouse surgeries. M.L.M. and R.S.P. provided stocks of RSV line 19, as well as guidance regarding virus propagation and use in mice. S.E.W. analyzed data and edited the manuscript. A.R. designed experiments, analyzed data and wrote the manuscript. P.R. conceived of the study, designed experiments, analyzed data and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Anuradha Ray or Prabir Ray.

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DOI

https://doi.org/10.1038/nm.2896

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