Pulmonary eosinophilia requires interleukin-5, eotaxin-1, and CD4+ T cells in mice immunized with respiratory syncytial virus G glycoprotein.
Severe illness, type 2 cytokine production, and pulmonary eosinophilia are adverse immune responses resulting from respiratory syncytial virus (RSV) challenge of vvGs-immunized mice. We have shown IL-4 and IL-13 activity must be simultaneously inhibited to reduce disease severity. We now address the contributions of IL-5, eotaxin-1, and CD4+ and CD8+ T cells to the induction of disease-enhancing immune responses. Depletion of CD4+ T cells during immunization prevented IL-4, IL-13, and eotaxin-1 production, diminished eosinophilia, and reduced weight loss. Conversely, CD8+ T cell depletion did not decrease eosinophilia, weight loss, or type 2 cytokines but did dramatically reduce mucus production and increase eotaxin production. Anti-IL-5 administration at immunization or challenge significantly decreased pulmonary eosinophilia. Strikingly, there were not concomitant decreases in weight loss. Following RSV challenge eotaxin-1-deficient mice immunized with vvGs exhibited significantly less eosinophilia without decreased weight loss or type 2 cytokine production. We conclude CD4+ T cell production of IL-5 and induction of eotaxin-1 are required for vvGs-induced eosinophilia following RSV challenge, while CD8+ T cells appear to down-regulate eotaxin-1 and mucus production. In summary, we demonstrate that pulmonary eosinophilia 1) is a by-product of memory CD4+ T cell activation, 2) does not necessarily correlate with mucus production, and, most importantly, 3) is not required for the RSV G-induced illness in mice. These findings have important implications for the evaluation of candidate RSV vaccines.
Johnson
Teresa R
TR
Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20892-3017, USA. teresaj@nih.gov
Rothenberg
Marc E
ME
Graham
Barney S
BS
D000818:Animals; D018893:Bronchoalveolar Lavage; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D054413:Chemokine CCL11 / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D007114:Immunization; D018793:Interleukin-13 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D015848:Interleukin-5 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011657:Pulmonary Eosinophilia / Q000276:immunology* / Q000517:prevention & control / Q000821:virology; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology* / Q000473:pathology / Q000821:virology; D022261:Respiratory Syncytial Virus Vaccines / Q000008:administration & dosage / Q000276:immunology; D012136:Respiratory Syncytial Viruses / Q000276:immunology*; D014616:Vaccinia virus / Q000276:immunology; D014760:Viral Fusion Proteins / Q000276:immunology*; D019562:Viral Load; D015431:Weight Loss
C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; C502275:G glycoprotein, Respiratory syncytial virus; D018793:Interleukin-13; D015848:Interleukin-5; D022261:Respiratory Syncytial Virus Vaccines; D014760:Viral Fusion Proteins; D015847:Interleukin-4