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Cutting Edge: Engagement of NKG2A on CD8⁺ Effector T Cells Limits Immunopathology in Influenza Pneumonia¹

Jing Zhou^*, Mitsuo Matsuoka^2,*, Harvey Cantor, Robert Homer^, and Richard I. Enelow^3,*,

^* 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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, HA_204–212-H-2K^d tetramer; LCMV, lymphocytic choriomeningitis virus; MLN, mediastinal lymph node; NP, nucleoprotein; SPC, surfactant protein C.

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