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.
Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20892-3017, USA. teresaj@nih.gov
Teresa R
TR
Johnson
Marc E
ME
Rothenberg
Barney S
BS
Graham
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