Journal of Clinical Immunology, Vol. 16, No. 5, 1996 Special Article The Molecular Basis of Natural Killer (NK) Cell Recognition and Function LORENZO MORETTA, 1'2'5 MARIA CRISTINA MINGARL 3 DANIELA PENDE, t CRISTINA BOTT1NO, 1 ROBERTO BIASSONI, 1 and ALESSANDRO MORETTA 4 Accepted: February 16, 1996 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 HLA class I alleles leads to NK-mediated target cell lysis. Different types of receptors specific for groups of HLA-C, HLA-B, and, very recently, HLA-A alleles have been identified. While in most instances, they function as inhibitory receptors, an activatory form of the HLA-C-specific receptors has been identified in some donors. Molecular cloning of HLA-C-, HLA-B- or HLA-A-specific receptors has revealed new members of the immunoglobulin superfamily with two or three Ig-like domains, respectively, in their extracellular por- tion. While the inhibitory form is characterized by a long cytoplasmic tail associated with a non-polar transmembrane portion, the activatory one has a short tail asociated 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 do- main. A subset of activated T lymphocytes expresses NK-type class I-specific receptors. These receptors exert an inhibiting activity on T cell receptor-mediated functions and may provide ~IstitutoScientifico Tumori e Centro Biotecnologie Avanzate, Genova, Italy. 2Istituto di Patologia Generale, Universit5 di Genova, Genova, Italy. 3Dipartimento di Oncologia, Clin. e Sperimentale, Universita di Genova, Genova, Italy. 4Dipartimento di Scienze Biomediche e Biotecnologie, Universit~tdi Brescia, Brescia, Italy. 5To whom correspondence should be addressed. an important mechanism of downregulation of T cell responses. KEY WORDS: Natural killer (NK) cells; NK ceil recognition; NK cell function; NK cell receptors. 243 INTRODUCTION NK cells were originally described on a functional basis according to their ability to lyse certain tumor cell lines without % priori" immunization (1, 2). Since this activity was also present also in athymic mice, this suggested that a novel cell population, different from T lymphocytes, was responsible for this function. Since NK cells are capable of lysing tumor cells expressing allogeneic major histocompatibility (MttC) antigen and even tumor cells which lack MHC, their cytolytic activity has been often referred to as "non-MHC restricted" (3-6). NK cells were generally thought to provide a first line of defense against some viral infections (7), although the mechanism leading to this protective effect was unclear. Unlike T or B lymphocytes, NK cells do not express known receptors for antigen, i.e., surface immunoglobu- lins (Ig) or T cell receptors (TCR) (8). Although NK cell maturation can occur in the absence of a functional thymus, cell precursors capable of differentiating to- wards NK cells were found in CD3-4-8-16- immature thymocytes (9), and a common progenitor for T and NK cell lineages has been identified in human fetal thymus (10). Triggering of NK cells results not only in the induction of cytolytic activity, but also in the production of a number of cytokines which can exert a regulatory role in the immune response, in inflammation, and in hematopoiesis (3, 11). The NK cell-mediated lysis of 0271-9142/96/0900-0243509,50/0 9 1996 Plenum Publishing Corporation