A lung-specific neo-antigen elicits specific CD8+ T cell tolerance with preserved CD4+ T cell reactivity. Implications for immune-mediated lung disease.

Abstract

The 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 CD4ϩ T lymphocyte responses to HA and found them to be similar to wild type responses. However, CD8ϩ 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 ϩ 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 ϩ 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 ϩ T cell tolerance, with CD4 ϩ T cell and B cell reactivity to the antigen, and that CD4 ϩ T cell reactivity may remain intact to an antigen expressed in the thymus, even when CD8 ϩ T cell tolerance exists. This observation may have profound implications concerning immune-mediated lung diseases, particularly those mediated by CD4 ϩ T cells. ( J. Clin. Invest. 1996. 98:914-922.)

Structural and functional consequences of alveolar cell recognition by CD8(+) T lymphocytes in experimental lung disease.

“…This suggests that the lethal injury produced by the adoptively transferred CTL required specific antigen recognition and was not due to a nonspecific increase in susceptibility of tg ϩ mice to CD8 ϩ CTL-mediated injury as a result of transgene expression in lung type II cells during development. This result is consistent with our earlier finding that tg ϩ mice also show no increased acute susceptibility to influenza virus infection (26).…”

“…SPC-HA transgenic (tg ϩ ) mice in the H-2 d haplotype, expressing the A/Japan/305/57 HA under the transcriptional control of the SPC promoter were used in these studies (26). The transgenic animals were originally developed in the FVB strain (H-2q), and subsequently backcrossed three times with BALB/c (H-2d) mice.…”

“…In this model, the A/Japan/57 influenza hemagglutinin (HA) was expressed as a transgene in mice under the transcriptional control of the surfactant protein C (SPC) promoter in order to achieve lung-specific expression. The HA transgenic animals exhibited complete CD8 ϩ T cell tolerance to all MHC class I-restricted epitopes of HA (26). The adoptive transfer of HA-specific CD8…”

Cutting Edge: Pulmonary Immunopathology Mediated by Antigen-Specific Expression of TNF-α by Antiviral CD8+ T Cells

“…6B). Similarly, transfer of an irrelevant CD8 ϩ T cell clone (specific for influenza nucleoprotein) into HA ϩ mice resulted in no immunopathology (15,23), and only background levels of IFN-␥ and TNF-␣ (data not shown). Because CD8 ϩ T cell production of IFN-␥ is dependent upon Ag engagement (24), these data indicate that both T cell populations were equally capable of trafficking to the alveolar parenchyma and interacting with Ag presented by the alveolar epithelial cell, but that in the absence of TNF-␣ expression, T cell Ag recognition did not result in epithelial activation.…”

Interference with Intraepithelial TNF-α Signaling Inhibits CD8+T-Cell-Mediated Lung Injury in Influenza Infection

“…The SP-C-14.7K and SP-C-HA mice have been backcrossed onto the BALB/c background for 10 generations. The double transgenic (SP-C-HA-14.7) strain was generated by interbreeding mice expressing either HA or 14.7 under the transcriptional control of the surfactant protein C (SP-C) promoter, which directs expression to the distal airway (alveolar and bronchiolar) epithelium (10,16). All experiments were conducted in strict accordance with the guidelines of the National Institute of Health (NIH) and the Dartmouth Medical School Institutional Animal Care and Use Committee (IACUC), including the requirement that any animal that lost 20% of its initial weight after infection would be euthanized.…”