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

Abstract

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-1b molecules with a t1/2 of ∼1.5 h at 37°C. In comparison, complexes of an optimal peptide (SIINFEKL) bound to the MHC class Ia molecule H-2Kb dissociated with a t1/2 in the range from 11 to 31 h. In contrast to Kb, the stability of cell surface Qa-1b molecules was independent of bound peptides, and several observations suggested that empty cell surface Qa-1b molecules might be unusually stable. Consistent with the rapid dissociation rate of Qdm from Qa-1b, cells become susceptible to lysis by CD94/NKG2A+ NK cells under conditions in which new Qa-1b/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.

Critical Role of Qa1b in the Protection of Mature Dendritic Cells from NK Cell‐Mediated Killing

“…Previous studies have shown that class I expression on DC protects from NK cell-mediated lysis in vitro [18, 20, [26]. This finding was further tested and confirmed in this study.…”

“…DC were checked for viability prior to use. For the stabilization of Qa1 b on the surface of the DC, DC were incubated overnight in the presence of the Qdm peptide (AMAPRTLLL) or its control peptide Qdm-4C (AMACRTLLL) as previously described [26].…”

The Inhibitory Receptor NKG2A Determines Lysis of Vaccinia Virus-Infected Autologous Targets by NK Cells

“…However, it has recently been shown that Qa-1 and HLA-E are unstable at the cell surface in comparison to classical MHC class I. These nonclassical class Ib molecules thus require a continuous supply of cognate peptide to maintain cell surface expression and thence mediate effective NK cell inhibition (45). One possibility to explain the specificity of MHC class I down-regulation is that vaccinia virus inhibits host protein synthesis (46,47).…”

IRF-3-dependent and augmented target genes during viral infection

“…The non-classical major histocompatability class I proteins serve as ligands for receptors on natural killer cells and g/d T cells. 29,30 It is clear from this small set of genes that the IRF-3 transcription factor acts to elicit widespread immune responses.…”