This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Influenza pneumonia results in considerable lung injury, a significant component of which is mediated by CD8+ T cell antigen recognition in the distal airways. TNF-alpha produced by antigen-specific CD8+ T cells appears to be the primary effector activity responsible for this immunopathology, and we have examined the negative regulation of CD8+ TNF production by CD94/NKG2A engagement by its receptor, Qa-1b. NKG2A expression is induced on CD8+ T cells in the lungs of influenza-infected mice, and expression levels fall as the virus is cleared. Expression was not observed in CD8+ T cells harvested from MLN or spleen at any time. TNF production by antiviral CD8+ T cells was significantly enhanced by NKG2A blockade, and mice deficient in its ligand, Qa-1b, manifest significantly greater immunopathology upon severe infection with influenza followed by transfer of activated effector CD8+ T cells. Furthermore, blockade of NKG2A ligation resulted in enhancement of pathology induced by activated CD8+ effector cell recognition of alveolar antigen in the absence of infectious virus. These data demonstrate that CD94/NKG2A transduces a biologically important signal to activated CD8+ T cells which limits their effector activity in vivo and mitigates immunopathology in severe influenza infection.
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