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

Abstract

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 host. Transgenic and gene knock-out mice have provided conclusive evidence that 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 Ly49 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 within each of two mutually none-exclusive models: cellular adaptation and clonal selection. Recent studies supporting cellular adaptation bring the focus on different possibilities within this general mechanism, such as anergy, receptor calibration and, most importantly, whether the specificity of each NK cell is permanently fixed or subject to continuous regulation.

In vivo tumor cell rejection induced by NK cell inhibitory receptor blockade: Maintained tolerance to normal cells even in the presence of IL‐2

“…Although normal, resting spleen cells were not rejected upon Ly49C/I blockade other cell types may be more sensitive. Allogeneic and MHC-deficient BM cells can be rejected by NK cells [33,34] and activated T cells may express ligands for activating NK receptors and be more sensitive to NK-mediated lysis [32]. In our system, however, inhibitory receptor blockade did not induce rejection of CFSE-labeled syngeneic BM cells or Con A-activated T cells (Fig.…”

The centromeric part of the human NK gene complex: linkage of LOX-1 and LY49L with the CD94/NKG2 region

“…3,5,18 Other forms, such as the CD69, the AICL, and the LLT1 genes, 10,13,15,34 are more widely expressed and may possess different functions. Furthermore, we have now located the lectin-type receptor for oxidized low-density lipoprotein, which is expressed on endothelial cells and macrophages, 35 genes.…”

“…NK cell receptors that recognize MHC class I or related molecules on target cells [2][3][4][5][6] can be grouped into two structurally distinct classes, namely the immunoglobulin-(Ig)-like and the C-type lectin receptors. The killer immunoglobulinlike receptors (KIR) have been found to be expressed on human NK cells and different variants display either repressive or triggering functions.…”

Allelic Variation in the Ectodomain of the Inhibitory Ly-49G2 Receptor Alters Its Specificity for Allogeneic and Xenogeneic Ligands

“…NK cells express a variety of inhibitory receptors specific for classical (class Ia) and nonclassical (class Ib) MHC-encoded molecules (1). Regulation of NK activities can be explained in part by the "missing self" hypothesis (5). For example, NK inhibitory receptors engaged by levels of class I MHC proteins found on healthy cells prevent NK activation, whereas pathologically altered cells deficient in class I expression are not protected by this mechanism.…”