T he A/Japan/57 influenza hemagglutinin (HA) was expressed in BALB/c mice under the transcriptional control of the surfactant protein C (SP-C) promoter, resulting in expression of HA in type II alveolar epithelial cells, as well as low level variable expression in other tissues, including the thymus in some of the founder lines. Transgenic animals were able to recover from infection with A/Japan/57 influenza, and they were able to mount antibody responses to A/Japan/57 HA in titers similar to wild type. We therefore tested their CD4+ T lymphocyte responses to HA and found them to be similar to wild type responses. However, CD8+ T cells from A/Japan/57-infected transgenic animals were unable to express cytolytic activity against target cells expressing the A/Japan/57 HA. The CD8+ T cell tolerance was also extremely specific, since transgenics immunized with an influenza strain containing a single amino acid substitution in a dominant HA epitope were able to mount full cytolytic responses to that epitope, but not the wild-type epitope. Adoptive transfer of CD8+ T cell clones into transgenic animals resulted extensive interstitial pneumonitis that was antigen-specific and associated with significant morbidity and mortality. We conclude that a lung-specific transgene may lead to specific CD8+ T cell tolerance, with CD4+ T cell and B cell reactivity to the antigen, and that CD4+ T cell reactivity may remain intact to an antigen expressed in the thymus, even when CD8+ T cell tolerance exists. This observation may have profound implications concerning immune-mediated lung diseases, particularly those mediated by CD4+ T cells.