Journal
JOURNAL OF IMMUNOLOGY
Volume 174, Issue 11, Pages 7234-7241Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.174.11.7234
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- NIAID NIH HHS [AI47226] Funding Source: Medline
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Respiratory syncytial virus (RSV) is the major cause of severe lower airway disease in infants and young children, but no safe and effective RSV vaccine is yet available. The difficulties involved in RSV vaccine development were recognized in an early vaccine trial, when children immunized with a formalin-inactivated virus preparation experienced enhanced illness after natural infection. Subsequent research in animal models has shown that the vaccine-enhanced disease is mediated at least in part by memory cells producing Th2 cytokines. Previously we had observed enhanced, eosinophilic lung pathology during primary infection of IFN-deficient STAT1(-/-) mice that are incapable of generating Th1 CD4(+) cells. To determine whether these effects depended only on Th2 cytokine secretion or involved other aspects of IFN signaling, we infected a series of 129SvEv knockout mice lacking the IFN-alpha beta R (IFN-alpha beta R-/-), the IFN-gamma R (IFN-gamma R-/-), or both receptors (IFN-alpha beta gamma R-/-). Although both the IFN-gamma R-/- and the IFN-alpha beta gamma R-/- animals generated strong Th2 responses to RSV-F protein epitopes, predominantly eosinophilic lung disease was limited to mice lacking both IFNRs. Although the absolute numbers of eosinophils in BAL fluids were similar between the strains, very few CD8(+) T cells could be detected in lungs of IFN-alpha beta gamma R-/- animals, leaving eosinophils as the predominant leukocyte. Thus, although CD4(+) Th2 cell differentiation is necessary for the development of allergic-type inflammation after infection and appears to be unaffected by type I IFNs, innate IFNs clearly have an important role in determining the nature and severity of RSV disease.
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