Receptors for Hla Class-I Molecules in Human Natural Killer Cells

Abstract

Natural killer cells are likely to play an important role in the host defenses because they kill virally infected or tumor cells but spare normal self-cells. The molecular mechanism that explains why NK cells do not kill indiscriminately has recently been elucidated. It is due to several specialized receptors that recognize major histocompatibility complex (MHC) class I molecules expressed on normal cells. The lack of expression of one or more class I alleles leads to NK-mediated target cell lysis. During NK cell development, the class I-specific receptors have adapted to self-class I molecules on which they recognize epitopes shared by groups of class I alleles. As such, they may fail to recognize either self-molecules that bound unusual peptides or allogeneic class I molecules unrelated to self-alleles. Different types of receptors specific for groups of HLA-C or HLA-B alleles have been identified. While in most instances, they function as inhibiting receptors, an activating form of the HLA-C-specific receptors has been identified in some donors. Molecular cloning of HLA-C- and HLA-B-specific receptors has revealed new members of the immunoglobulin superfamily with two or three Ig-like domains, respectively, in their extracellular portion. While the inhibiting form is characterized by a long cytoplasmic tail associated with a nonpolar transmembrane portion, the activating one has a short tail associated with a Lys-containing transmembrane portion. Thus, these human NK receptors are different from the murine Ly49 that is a type II transmembrane protein characterized by a C type lectin domain. A subset of cytolytic T lymphocytes expresses NK-type class I-specific receptors. These receptors exert an inhibiting activity on T cell receptor-mediated functions and offer a valuable model to analyze the regulatory mechanisms involved in receptor-mediated cell activation and inactivation.

Immunoregulatory function of mesenchymal stem cells

“…NK cells are major effectors of the innate arm of the immune system that play a key role in the elimination of virus-infected and malignant cells [55][56][57]. As for T cells and B cells, NK cell progenitors originate in the BM where they establish close interactions with mesenchymal stromal cells.…”

Requirements for control of B‐cell lymphoma by NK cells

“…Inhibitory receptors interacting with MHC selfmolecules interfere with positive signaling, thus protecting normal tissue from NK-cell attack. As predicted by the ''missing self hypothesis'', interaction of NK cells with target cells expressing reduced levels of self MHC, such as virus-infected or tumor cells, ignites the lytic machinery [3][4][5][6]. Inhibitory receptors of mouse NK cells comprise several Ly49 receptors, CD94/NKG2A [7] or CD48 [8].…”

Gntb-A, a Novel Sh2d1a-Associated Surface Molecule Contributing to the Inability of Natural Killer Cells to Kill Epstein-Barr Virus–Infected B Cells in X-Linked Lymphoproliferative Disease

“…Progress is mainly consequent to the discovery of a series of receptors, expressed at the NK cell surface, regulating NK cell functions. Some of these receptors inhibit NK cells by monitoring the expression of MHC class I molecules on normal cells 1 2 3. Other receptors are responsible for NK cell activation 4.…”