Mats Y. Olsson-Alheim

Host MHC class I gene control of NK-cell specificity in the mouse

Summary: The missing self model predicts chat NK cells adapt somatically to the type as well as levels of MHC class I products expressed by their host, Transgenic and gene knock‐out mice have provided conclusive evidence chat MHC class I genes control specificity and tolerance of NK cells. The article describes this control and discusses the POSSIBLE Mechanisms behind it. starting from a genetic model to study how natural resistance to tumors is influenced by MHC class I expression in the host as well as in the target cells. Data on host gene regulation of NK‐cell functional specificity as well as Lγ49 receptor expression are reviewed, leading up to the central question: how does the system develop and maintain “useful” NK cells, while avoiding “harmful” and “useless” ones? The available data can be fitted with in each of two mutually non‐exclusive models: cellular adaptation and clonal selection. Recent studies supporting cellular adaptation bring the focus on different possibilities within this general mechanism, such as energy, receptor calibration and, most importantly, whether the specificity of each NK cell is permanently fixed or subject to continuous regulation.

Impaired MHC class I (H-2Dd)-mediated protection against Ly-49A+ NK cells after amino acid substitutions in the antigen binding cleft.

The MHC class I molecule H‐2Dd (Dd) acts as a ligand for the inhibitory NK cell receptor Ly‐49A. We have constructed altered Dd molecules by site‐directed mutagenesis, replacing residues with the corresponding amino acids from the Db molecule, which fails to inhibit via Ly‐49A. Mutations at positions 73 and 156 (DdS73WD156Y) impaired the protective effect of the Dd molecule, as evaluated by testing lymphoma cells transfected with the mutant gene for sensitivity to killing by Ly‐49A+ NK cells in vitro and rejection by NK cells in vivo. The altered residues form a hydrophobic ridge across the floor of the antigen binding cleft. A mutation in the α helix of the α2 domain, facing the solvent and without direct contact with the peptide (DdA150S) had no effect. Dd recognition by Ly‐49A+ NK cells is considered to be peptide dependent, but not peptide specific. Our results indicate that alterations of residues buried in the antigen binding cleft can induce changes in peptide binding patterns and/or conformational changes in the Dd molecule that make the trimolecular complex less permissive for inhibition of Ly‐49A+ NK cells.