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 respon se 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 t ransgenic mice exhibited similar local recruitment of CD4(+) and CD8(+) T c ells and only slightly decreased virus-specific CTL activity. However, duri ng secondary challenge with a heterologous influenza virus, the local infil tration with virus-specific, MHC class I-restricted CD8(+) T cells was sign ificantly decreased compared to that of nontransgenic littermates. The abil ity of IL-4 transgenic mice to clear the heterologous infection was delayed but not abrogated. This was associated with a faster virus-neutralizing an tibody response in IL-4 transgenic mice and with their ability to mount sig nificant Th1 responses even in the presence of increased local IL-4 express ion. Our observations demonstrate a negative regulatory effect of IL-4 on m emory Tc1/CD8(+) T cells, but are also consistent with complementary mechan isms important for virus clearance such as virus-neutralizing antibodies. T he 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. (C) 2000 Academic Press.