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Fas Ligand Is Required for the Development of Respiratory Syncytial Virus Vaccine-Enhanced Disease¹

Matthew R. Olson^* and Steven M. Varga^2,*,

^* Department of Microbiology, and Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA 52242

Children immunized with a formalin-inactivated respiratory syncytial virus (RSV) vaccine experienced enhanced disease and exhibited pulmonary eosinophilia upon natural RSV infection. BALB/c mice immunized with either formalin-inactivated RSV or a recombinant vaccinia virus (vacv) expressing the RSV attachment (G) protein develop extensive pulmonary eosinophilia after RSV challenge that mimics the eosinophilic response observed in the children during the 1960s vaccine trials. Fas ligand (FasL) is a major immune effector molecule that can contribute to the clearance of respiratory viruses. However, the role of FasL in the development of RSV vaccine-enhanced disease has not been elucidated. RSV challenge of vacvG-immunized gld mice, that lack functional FasL, results in diminished systemic disease as well as pulmonary eosinophilia. The magnitude of the secondary RSV G-specific CD4 T cell response was diminished in gld mice as compared with wild-type controls. Furthermore, we show that CD4 T cells isolated after RSV challenge of vacvG-immunized gld mice exhibit enhanced expression of Annexin V and caspase 3/7 indicating that FasL is important for either the survival or the expansion of virus-specific secondary effector CD4 T cells. Taken together, these data identify a previously undefined role for FasL in the accumulation of secondary effector CD4 T cells and the development of RSV vaccine-enhanced disease.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant AI 063520 from the National Institutes of Health.

² Address correspondence and reprint requests to Dr. Steven M. Varga, 3-532 Bowen Science Building, Department of Microbiology, 51 Newton Road, University of Iowa, Iowa City, IA 52242. E-mail address: steven-varga{at}uiowa.edu

³ Abbreviations used in this paper: RSV, respiratory syncytial virus; FI-RSV, formalin-inactivated RSV; vacv, vaccinia virus; G, RSV attachment protein; BAL, bronchial alveolar lavage; MedLN, mediastinal lymph node; WT, wild type; FasL, Fas ligand; β-gal, β-galactosidase.