The nonclassical MHC class I molecule Qa-1 forms unstable peptide complexes.
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.
Kambayashi
Taku
T
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Kraft-Leavy
Jennifer R
JR
Dauner
Joseph G
JG
Sullivan
Barbara A
BA
Laur
Oskar
O
Jensen
Peter E
PE
D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology; D015703:Antigens, CD / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D003601:Cytotoxicity Tests, Immunologic; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004640:Emetine / Q000494:pharmacology; D006183:H-2 Antigens / Q000378:metabolism; D006680:HLA Antigens / Q000378:metabolism; D006207:Half-Life; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055654:NK Cell Lectin-Like Receptor Subfamily C; D051920:NK Cell Lectin-Like Receptor Subfamily D; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000276:immunology; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000378:metabolism; D055607:Receptors, Natural Killer Cell; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D000097625:HLA-E Antigens
D015703:Antigens, CD; D004640:Emetine; D006183:H-2 Antigens; D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; D037181:Lectins, C-Type; D055654:NK Cell Lectin-Like Receptor Subfamily C; D051920:NK Cell Lectin-Like Receptor Subfamily D; D010455:Peptides; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D011994:Recombinant Proteins; D000097625:HLA-E Antigens; C032876:H-2Kb protein, mouse; C527054:KLRC1 protein, human; C497869:KLRD1 protein, human; C527057:Klrc1 protein, mouse; C497870:Klrd1 protein, mouse; C032907:Q surface antigens; C090580:Qdm protein, mouse