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

Nature Medicine volume 18, pages 1525–1530 (2012)Cite this article

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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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Figure 1: Recurrent RSV infection compromises maternally transferred tolerance to inhaled allergen.
Figure 2: RSV infection triggers inflammation in lung-draining lymph nodes.
Figure 3: RSV infection alters the phenotype and function of Treg cells in the lung.
Figure 4: Treg cells acquire a TH2-like effector phenotype in tolerized RSV-infected mice.
Figure 5: Host IL-4Rα signaling is important to breach tolerance.

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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.).

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Author notes

  1. Anupriya Khare and Timothy B Oriss: These authors contributed equally to this work.

Authors and 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.

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Correspondence to Anuradha Ray or Prabir Ray.

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Krishnamoorthy, N., Khare, A., Oriss, T. et al. Early infection with respiratory syncytial virus impairs regulatory T cell function and increases susceptibility to allergic asthma. Nat Med 18, 1525–1530 (2012). https://doi.org/10.1038/nm.2896

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