Mechanisms of allergy and clinical immunology
Responsiveness to respiratory syncytial virus in neonates is mediated through thymic stromal lymphopoietin and OX40 ligand

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Background

Recent studies revealed a critical role for thymic stromal lymphopoietin (TSLP) released from epithelial cells and OX40 ligand (OX40L) expressed on dendritic cells (DCs) in TH2 priming and polarization.

Objectives

We sought to determine the importance of the TSLP-OX40L axis in neonatal respiratory syncytial virus (RSV) infection.

Methods

Mice were initially infected with RSV as neonates or adults and reinfected 5 weeks later. Anti-OX40L or anti-TSLP were administered during primary or secondary infection. Outcomes included assessment of airway function and inflammation and expression of OX40L, TSLP, and IL-12.

Results

OX40L was expressed mainly on CD11c+MHC class II (MHCII)+CD11b+ DCs but not CD103+ DCs. Treatment of neonates with OX40L antibody during primary RSV infection prevented the subsequent enhancement of airway hyperresponsiveness and the development of airway eosinophilia and mucus hyperproduction on reinfection. Administration of anti-TSLP before neonatal RSV infection reduced the accumulation of lung DCs, decreased OX40L expression on lung DCs, and attenuated the enhancement of airway responses after reinfection.

Conclusions

In mice initially infected as neonates, TSLP expression induced by RSV infection is an important upstream event that controls OX40L expression, lung DC migration, and TH2 polarization, accounting for the enhanced response on reinfection.

Section snippets

Antibodies

Rat anti-mouse OX40L (RM134L) and anti-TSLP mAb (M702) were used.19

Animals

BALB/c mice were obtained from the Jackson Laboratory (Bar Harbor, Me).

Virus preparation

Human RSV A2 Strain (catalog no. VR-1302) and HEp-2 cells (catalog no. CCL-23) were obtained from the American Type Culture Collection (Rockville, Md), and stocks of purified RSV were prepared and viral titers determined.8

RSV infection and treatments

Mice were inoculated with 106 plaque-forming units of purified RSV at the indicated age. Anti-OX40L or control antibody was administered

RSV infection induces OX40L expression on lung DCs

Mice were infected as neonates (<1 week of age) or at 5 weeks of age to determine the levels of OX40L expression on lung DCs after RSV infection. On each day after infection, single-cell suspensions from lung homogenates were prepared, and the frequency of lung DC subsets expressing OX40L was obtained according to the gating strategy described in Fig E1 in this article’s Online Repository at www.jacionline.org. In both age groups, RSV infection resulted in an increased percentage of OX40L+CD11c+

Discussion

The interplay between RSV infection and asthma, especially the development of asthma, is not entirely clear.30 Severe RSV infection and the need for hospitalization have been linked to asthma development,2, 3, 4 but it is unclear whether reinfection plays a similar role as it does in enhancing respiratory disease severity. To approach these issues in an experimental model, we examined the responses to reinfection in mice initially infected as neonates or at a later age and demonstrated dramatic

References (54)

  • N. Sigurs et al.

    Severe respiratory syncytial virus bronchiolitis in infancy and asthma and allergy at age 13

    Am J Respir Crit Care Med

    (2005)
  • P.D. Sly et al.

    Childhood asthma following hospitalization with acute viral bronchiolitis in infancy

    Pediatr Pulmonol

    (1989)
  • B. Adkins et al.

    Neonatal adaptive immunity comes of age

    Nat Rev Immunol

    (2004)
  • A. Dakhama et al.

    The enhancement or prevention of airway hyperresponsiveness during reinfection with respiratory syncytial virus is critically dependent on the age at first infection and IL-13 production

    J Immunol

    (2005)
  • Y.M. Lee et al.

    IFN-γ production during initial infection determines the outcome of reinfection with respiratory syncytial virus

    Am J Respir Crit Care Med

    (2008)
  • A. Dakhama et al.

    Virus-specific IgE enhances airway responsiveness on reinfection with respiratory syncytial virus in newborn mice

    J Allergy Clin Immunol

    (2009)
  • J. Han et al.

    Montelukast during primary infection prevents airway hyperresponsiveness and inflammation after reinfection with respiratory syncytial virus

    Am J Respir Crit Care Med

    (2010)
  • J.S. Tregoning et al.

    The role of T cells in the enhancement of respiratory syncytial virus infection severity during adult reinfection of neonatally sensitized mice

    J Virol

    (2008)
  • M. Croft et al.

    The significance of OX40 and OX40L to T-cell biology and immune disease

    Immunol Rev

    (2009)
  • M. Croft

    Control of immunity by the TNFR-related molecule OX40 (CD134)

    Annu Rev Immunol

    (2010)
  • A.G. Jember et al.

    Development of allergic inflammation in a murine model of asthma is dependent on the costimulatory receptor OX40

    J Exp Med

    (2001)
  • R.S. Arestides et al.

    Costimulatory molecule OX40L is critical for both Th1 and Th2 responses in allergic inflammation

    Eur J Immunol

    (2002)
  • A. Hoshino et al.

    Critical role for OX40 ligand in the development of pathogenic Th2 cells in a murine model of asthma

    Eur J Immunol

    (2003)
  • S. Salek-Ardakani et al.

    OX40 (CD134) controls memory T helper 2 cells that drive lung inflammation

    J Exp Med

    (2003)
  • B. Zhou et al.

    Thymic stromal lymphopoietin as a key initiator of allergic airway inflammation in mice

    Nat Immunol

    (2005)
  • A. Al-Shami et al.

    A role for TSLP in the development of inflammation in an asthma model

    J Exp Med

    (2005)
  • D.P. Huston et al.

    Thymic stromal lymphopoietin: a potential therapeutic target for allergy and asthma

    Curr Allergy Asthma Rep

    (2006)

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    Supported by National Institutes of Health (NIH) grants AI-77609, HL-36577, and HL-61005. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the NIH.

    Disclosure of potential conflict of interest: S. F. Ziegler has received research support from the National Institutes of Health (NIH), has received lecture fees from the American Academy of Allergy, Asthma & Immunology, and has received travel expenses from the Federation of Clinical Immunology Societies. E. W. Gelfand has received research support from the NIH. The rest of the authors declare that they have no relevant conflicts of interest.

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    Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.