Host genetic determinants of vaccine-induced eosinophilia during respiratory syncytial virus infection.
In BALB/c mice, sensitization with the attachment protein (G) of respiratory syncytial virus (RSV) leads to CD4+ T cell-mediated lung eosinophilia during subsequent challenge with RSV. To determine the host genetic influences on this model of lung eosinophilia, we tested 15 different inbred mouse strains. Eosinophilia developed in all H-2d (BALB/c, DBA/2n, and B10.D2), but not in H-2k (CBA/Ca, CBA/J, C3H, BALB.K, or B10.BR) mouse strains. Among H-2b mice, 129 and BALB.B developed eosinophilia, whereas C57BL/6 and C57BL/10 did not. Testing first generation crosses between sensitive and resistant strains showed that eosinophilia developed in all H-2dxk (n = 5), irrespective of background genes, but not in H-2dxb (n = 2) mice. In vivo depletion of CD8+ T cells or IFN-gamma rendered C57BL/6, but not BALB.K mice, susceptible to eosinophilia. Analysis of B10 recombinant mice showed that the Dd allele (in B10.A(5R) mice) prevented CD8+ T cell accumulation in the lung, resulting in intense lung eosinophilia. However, the Db allele (in B10.A(2R) and B10.A(4R) mice) supported CD8+ T cell expansion and prevented eosinophilia. Intracellular cytokine staining showed that lung eosinophilia correlated with reduced IFN-gamma and increased IL-10 expression in lung T cells. These results are compatible with the unifying model that Th2 cells mediate the disease but can be inhibited by CD8+ T cells secreting IFN-gamma. Our findings have important implications for the development of protective, nonpathogenic vaccines for RSV disease.
Hussell
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Respiratory Medicine, National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, London, United Kingdom. t.hussell@ic.ac.uk
Georgiou
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Sparer
T E
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Matthews
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Pala
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P
Openshaw
P J
PJ
D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D003433:Crosses, Genetic; D016207:Cytokines / Q000096:biosynthesis; D004802:Eosinophilia / Q000235:genetics / Q000276:immunology* / Q000821:virology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics / Q000276:immunology*; D006183:H-2 Antigens / Q000096:biosynthesis / Q000235:genetics; D015707:HN Protein; D007113:Immunity, Innate; D007424:Intracellular Fluid / Q000378:metabolism; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D009297:Nasal Mucosa / Q000821:virology; D011995:Recombination, Genetic; D018357:Respiratory Syncytial Virus Infections / Q000235:genetics / Q000276:immunology*; D012136:Respiratory Syncytial Viruses / Q000276:immunology* / Q000502:physiology; D014616:Vaccinia virus / Q000502:physiology; D014759:Viral Envelope Proteins; D014764:Viral Proteins / Q000276:immunology; D014765:Viral Vaccines / Q000276:immunology*; D014779:Virus Replication / Q000276:immunology
D000914:Antibodies, Viral; D016207:Cytokines; D006183:H-2 Antigens; D015707:HN Protein; D014759:Viral Envelope Proteins; D014764:Viral Proteins; D014765:Viral Vaccines; C116204:attachment protein G