RECEPTORS FOR HLA CLASS-I MOLECULES IN HUMAN NATURAL-KILLER-CELLS

Natural killer cells are likely to play an important role in the host defenses because they kill virally infected or tumor cells but spare n ormal self-cells. The molecular mechanism that explains why NK cells d o 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 o f expression of one or more class I alleles leads to NK-mediated targe t cell lysis. During NK cell development, the class I-specific recepto rs have adapted to self-class I molecules on which they recognize epit opes shared by groups of class I alleles. As such, they may fail to re cognize either self-molecules that bound unusual peptides or allogenei c class I molecules unrelated to self-alleles. Different types of rece ptors specific for groups of HLA-C or HLA-B alleles have been identifi ed. While in most instances, they function as inhibiting receptors, an activating form of the HLA-C-specific receptors has been identified i n some donors. Molecular cloning of HLA-C- and HLA-B-specific receptor s 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 tai l associated with a nonpolar transmembrane portion, the activating one has a short tail associated with a Lys-containing transmembrane porti on. Thus, these human NK receptors are different from the murine Ly49 that is a type II transmembrane protein characterized by a C type lect in 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 anal yze the regulatory mechanisms involved in receptor-mediated cell activ ation and inactivation.