HOST MHC CLASS-I GENE-CONTROL OF NK-CELL SPECIFICITY IN THE MOUSE

The missing self model predicts that NK cells adapt somatically to the type as well as levels of MHC class I products expressed by their hos t. Transgenic and gene knock-out mice have provided conclusive evidenc e that MHC class I genes control specificity and tolerance of NK cells . The article describes this control and discusses the possible mechan isms behind it, starting from a genetic model to study how natural res istance to tumors is influenced by MHC class I expression in the host as well as in the larger cells. Data on host gene regulation of NK-cel l functional specificity as well as Ly49 receptor expression are revie wed, leading up to the central question: how does the system develop a nd maintain ''useful'' NK cells, while avoiding ''harmful'' and ''usel ess'' ones? The available data can be fitted within each of two mutual ly non-exclusive models: cellular adaptation and clonal selection. Rec ent studies supporting cellular adaptation bring the focus on differen t possibilities within this general mechanism, such as anergy, recepto r calibration and, most importantly whether the specificity of each NK cell is permanently fixed or subject to continuous regulation.