The Nonclassical MHC Class I Molecule Qa-1 Forms Unstable Peptide Complexes

• Published in: The Journal of immunology (1950) Vol. 172; no. 3; pp. 1661 - 1669
• Main Authors: Kambayashi, Taku, Kraft-Leavy, Jennifer R, Dauner, Joseph G, Sullivan, Barbara A, Laur, Oskar, Jensen, Peter E
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 01-02-2004
• Subjects: Animals; Antigen Presentation - genetics; Antigen Presentation - immunology; Antigens, CD - metabolism; CD94 antigen; Cell Line; Cell Membrane - immunology; Cell Membrane - metabolism; Cytotoxicity Tests, Immunologic; Dendritic Cells - drug effects; Dendritic Cells - immunology; Dendritic Cells - metabolism; Emetine - pharmacology; H-2 Antigens - metabolism; Half-Life; Histocompatibility Antigens Class I - genetics; Histocompatibility Antigens Class I - metabolism; HLA Antigens - metabolism; HLA-E Antigens; Humans; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Lectins, C-Type - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; NK Cell Lectin-Like Receptor Subfamily C; NK Cell Lectin-Like Receptor Subfamily D; NKG2A antigen; Peptides - genetics; Peptides - metabolism; Protein Binding - immunology; Receptors, Immunologic - biosynthesis; Receptors, Immunologic - metabolism; Receptors, Natural Killer Cell; Recombinant Proteins - metabolism; Transfection
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.172.3.1661

The MHC class Ib molecule Qa-1 is the primary ligand for mouse CD94/NKG2A inhibitory receptors expressed on NK cells, in addition to presenting Ags to a subpopulation of T cells. CD94/NKG2A receptors specifically recognize Qa-1 bound to the MHC class Ia leader sequence-derived peptide Qdm. Qdm is the dominant peptide loaded onto Qa-1 under physiological conditions and this peptide has an optimal sequence for binding to Qa-1. Peptide dissociation experiments demonstrated that Qdm dissociates from soluble or cell surface Qa-1(b) molecules with a t(1/2) of approximately 1.5 h at 37 degrees C. In comparison, complexes of an optimal peptide (SIINFEKL) bound to the MHC class Ia molecule H-2K(b) dissociated with a t(1/2) in the range from 11 to 31 h. In contrast to K(b), the stability of cell surface Qa-1(b) molecules was independent of bound peptides, and several observations suggested that empty cell surface Qa-1(b) molecules might be unusually stable. Consistent with the rapid dissociation rate of Qdm from Qa-1(b), cells become susceptible to lysis by CD94/NKG2A(+) NK cells under conditions in which new Qa-1(b)/Qdm complexes cannot be continuously generated at the cell surface. These results support the hypothesis that Qa-1 has been selected as a specialized MHC molecule that is unable to form highly stable peptide complexes. We propose that the CD94/NKG2A-Qa-1/Qdm recognition system has evolved as a rapid sensor of the integrity of the MHC class I biosynthesis and Ag presentation pathway.