Local IL-4 expression in the lung reduces pulmonary influenza-virus-specific secondary cytotoxic T cell responses.
We studied the effect of lung-specific IL-4 expression on the T cell response during primary and secondary heterologous infection with influenza virus by using transgenic mice that express IL-4 under a lung-specific promoter. Subsequent to primary infection with a type A/H1N1 influenza virus these transgenic mice exhibited similar local recruitment of CD4(+) and CD8(+) T cells and only slightly decreased virus-specific CTL activity. However, during secondary challenge with a heterologous influenza virus, the local infiltration with virus-specific, MHC class I-restricted CD8(+) T cells was significantly decreased compared to that of nontransgenic littermates. The ability of IL-4 transgenic mice to clear the heterologous infection was delayed but not abrogated. This was associated with a faster virus-neutralizing antibody response in IL-4 transgenic mice and with their ability to mount significant Th1 responses even in the presence of increased local IL-4 expression. Our observations demonstrate a negative regulatory effect of IL-4 on memory Tc1/CD8(+) T cells, but are also consistent with complementary mechanisms important for virus clearance such as virus-neutralizing antibodies. The reduction of memory CTL in the presence of IL-4 might have consequences for understanding the course of influenza infection in situations where T(H)2 immunity is increased.
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Department of Neuropharmacology, Division of Virology, IMM6, The Scripps Research Institute, La Jolla, CA 92037, USA.
Holz
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Christen
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Wolfe
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Temann
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Flavell
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von Herrath
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D000818:Animals; D000914:Antibodies, Viral / Q000097:blood / Q000276:immunology; D016207:Cytokines / Q000032:analysis / Q000235:genetics / Q000276:immunology; D007117:Immunization, Secondary; D007156:Immunologic Memory / Q000276:immunology; D009980:Influenza A virus / Q000276:immunology* / Q000502:physiology; D015847:Interleukin-4 / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017730:Ki-1 Antigen / Q000032:analysis; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009500:Neutralization Tests; D009928:Organ Specificity; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000473:pathology / Q000821:virology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D019562:Viral Load
D000914:Antibodies, Viral; D016207:Cytokines; D017730:Ki-1 Antigen; D012333:RNA, Messenger; D015847:Interleukin-4