Lorenzo Moretta

Allorecognition by NK cells: nonself or no self?

The issue of antigen recognition by NK cells is complex, fascinating and, as yet, unresolved. This article reviews recent research on the repertoire of human NK cell clones for the recognition of different allogeneic cells, and summarizes the studies, most of which have been performed in mice, that implicate the MHC in NK cell recognition. It goes on to provide a common conceptual framework within which these different systems may be understood.

Ontogeny, specific functions and receptors of human natural killer cells

Several of the generally accepted ideas on natural killer (NK) cells have been challenged by recent data that have substantially modified our view on these lymphoid cell populations. Although maturation of NK cells can occur in the absence of a functional thymus, clonogenic precursors capable of differentiating into mature CD3-16+56+ NK cells were found in CD3-4-8-16- populations isolated from human postnatal thymus. Analysis of the cytolytic activity of interleukin-2-activated NK cell populations and clones revealed that they can lyse normal cells (e.g., PHA blasts) isolated from certain individuals. In addition, NK clones isolated from single donors displayed different patterns of cytolytic activity against a panel of allogeneic cells, thus indicating that an NK cell repertoire exists. Genetic analyses of the determinants responsible for susceptibility/resistance to lysis together with the use of HLA-defective variants or HLA-transfectants revealed that the expression of given HLA class I alleles protects target cells from lysis by different groups of NK clones. Thus, NK cells express a clonally distributed ability to recognize HLA class I alleles. New monoclonal antibodies directed to members of a novel family of NK-specific p58 molecules allowed identification of the putative NK receptors for different major histocompatibility complex class I alleles. Indeed, a precise correlation has been established between expression of given p58 molecules (e.g., EB6 and GL183 molecules) and class I alleles recognized. In addition, anti-p58 monoclonal antibodies restored the NK-mediated lysis of class I-protected cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Natural killer cell immune regulation

Publisher Summary Natural killer (NK) cells are potent effector cells of innate immunity. Their function is finely regulated by a series of activating and inhibitory receptors. Inhibitory receptors recognize MHC-class I molecules on potential target cells and prevent cellular activation and cytolysis when, they express sufficient amounts of MHC class I at their surface. A remarkable exception is represented by myeloid dendritic cells (DCs) that are killed by activated NK cells if they have failed to undergo complete maturation (DC editing). NK–DC interactions are greatly potentiated by pathogen-derived products that activate several different cell types of innate immunity through expression of Toll-like receptors (TLRs). Besides NK and DC, these cells include plasmacytoid DCs (PDCs), eosinophils and mast cells. The resulting crosstalk between these cell types is mediated by cytokines, chemokines or direct cell-to-cell interactions, so-called Signal 5s to distinguish them from the signals important in the afferent immune response. This crosstalk has a great impact not only on the quality and strength of innate immune responses but also on subsequent adaptive immune responses. Thus, NK cells play an important role in defence against pathogens (and tumor) not only because of their effector function but also because of their regulatory capability within tissues on the nature and quality of innate and adaptive immune responses. Classical innate effector cells can now be viewed also as regulatory cells that play a key role in defence against pathogens. Further understanding of the interaction within innate immunity and at the interface between innate and adaptive immunity should be of considerable aid in designing novel therapeutic strategies and effective vaccines against infectious agents and, perhaps, tumor.

Chapter Thirty-Two – Natural killer cell immune regulation: Coordination of immune function in tissues

Publisher Summary Natural killer (NK) cells are potent effector cells of innate immunity. Their function is finely regulated by a series of activating and inhibitory receptors. Inhibitory receptors recognize MHC-class I molecules on potential target cells and prevent cellular activation and cytolysis when, they express sufficient amounts of MHC class I at their surface. A remarkable exception is represented by myeloid dendritic cells (DCs) that are killed by activated NK cells if they have failed to undergo complete maturation (DC editing). NK–DC interactions are greatly potentiated by pathogen-derived products that activate several different cell types of innate immunity through expression of Toll-like receptors (TLRs). Besides NK and DC, these cells include plasmacytoid DCs (PDCs), eosinophils and mast cells. The resulting crosstalk between these cell types is mediated by cytokines, chemokines or direct cell-to-cell interactions, so-called Signal 5s to distinguish them from the signals important in the afferent immune response. This crosstalk has a great impact not only on the quality and strength of innate immune responses but also on subsequent adaptive immune responses. Thus, NK cells play an important role in defence against pathogens (and tumor) not only because of their effector function but also because of their regulatory capability within tissues on the nature and quality of innate and adaptive immune responses. Classical innate effector cells can now be viewed also as regulatory cells that play a key role in defence against pathogens. Further understanding of the interaction within innate immunity and at the interface between innate and adaptive immunity should be of considerable aid in designing novel therapeutic strategies and effective vaccines against infectious agents and, perhaps, tumor.

Clonal Analysis of Human T Lymphocytes Inducing B Cell Growth

The central role of T lymphocytes in the control of antibody responses has been known since long time. Nevertheless, only during the last few years major progresses have been made towards 1) the understanding of the functional and pheno-typic characteristics of T cells which influence B cell growth and differentiation, 2) The nature of soluble factors involved in signalling between T and B lymphocytes. 3) The stages and mechanisms involved in B cell activation, proliferation and differentiation (1). For the most part, this favorable situation can be traced to the merging of new technologies. On the one hand, the use of monoclonal antibodies has provided omogeneous reagents for the unambiguous definition of the pheno-typic characteristics of T cell subsets and clones (2) and of B cells at different stages of activation. In addition, mAbs specific for some lymphokines and/or their cell surface receptors allowed a more precise definition of the involvement of these mediators in B cell growth or differentiation (3–6). At the same time, molecular ingeneering techniques provided scientists with some lymphokines in recombinant form (7): it thus became evident that several different activities could be attribued to single lymphokines. In addition, rapid advances in flow microfluorometry have provided a precise and objective means to quantify given surface markers and the extent to which the marker is expressed. Finally the improvement of T cell cloning techniques made it possible to grow virtually all T lymphocytes, thus allowing to identify both frequencies and subset distribution of T cells responsible for B cell proliferation and differentiation.