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* Department of Internal Medicine and
Department of Pathology, Yale University School of Medicine, New Haven, CT 06510;
Veterans Affairs Connecticut Healthcare System, West Haven, CT 06516; and
Dana Farber Cancer Institute, Boston, MA 02115
Influenza pneumonia results in considerable lung injury, a significant component of which is mediated by CD8+ T cell Ag recognition in the distal airways and alveoli. TNF-
produced by Ag-specific CD8+ T cells appears primarily responsible for this immunopathology, and we have examined the negative regulation of CD8+ TNF production by CD94/NKG2A engagement with its receptor, Qa-1b. TNF production by antiviral CD8+ T cells was significantly enhanced by NKG2A blockade in vitro, and mice deficient in the NKG2A ligand, Qa-1b, manifested significantly greater pulmonary pathology upon CD8+ T cell-mediated clearance in influenza pneumonia. Furthermore, blockade of NKG2A ligation resulted in the enhancement of lung injury induced by CD8+ effector cell recognition of alveolar Ag in vivo in the absence of infectious virus. These data demonstrate that CD94/NKG2A transduces a biologically important signal in vivo to activated CD8+ T cells that limits immunopathology in severe influenza infection.
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1 This work was supported by Public Health Service Grant AI069360 as well as by a Merit Award from the Department of Veterans Affairs.
2 Current address: Departments of Medicine and Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH 03756.
3 Address correspondence and reprint requests to Dr. Richard I. Enelow at the current address: Departments of Medicine and Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH 03756. E-mail address: richard.i.enelow{at}dartmouth.edu
4 Abbreviations used in this paper: i.n., intranasal(ly); BAL, bronchoalveolar lavage; BFA, brefeldin A; HA, hemagglutinin; HA204 Tet, HA204–212-H-2Kd tetramer; LCMV, lymphocytic choriomeningitis virus; MLN, mediastinal lymph node; NP, nucleoprotein; SPC, surfactant protein C.
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