Cells of the Immune System These cells then become Since they lack antigen receptors NK cells do no cepto iral tides.Oncethe dto the infecte molecular chan s in the surface cells,they have several mechanisms by which they can kill cell which are indicative of that cell being abnormal and their targets. granules in asm.T wh redu expr 01 gh th which enter the tar t cells th targe surface ligands for MHC the perforin pores to activate caspase enzymes involved in class I known as killer inhibitory receptors (KIRs)becaus apoptosis T cells also express a surface molecule called their bin ding to MHC class I on the surfac of a potential is the cytotoxica ivityo the NK ceptors on target cells In contrast to the limited expression of MHC class II they interact with infected or malignant cells with reduced molecules,most cells normally express atialagesiorTcelsgrihey MHC expression of MH( class I the lack of KIR engagement NK cell on oft with tar cells which lead to killing including CD2.CD16.CD69 and lectins (sugar-bindin y&T lymphocytes The anti ed antibody-dependent ytotoxicity (ADCC re abundant inepithelia ofthe gut,lungs Since they do not require activation by specificantigen in order to me their ects. thymus butothers migrate directly from the bone marrow e early ral infe to the gut and mature there.The antigen receptors of y T to limit the s read of the infection within the body until cells show much more limited diversity tha those of virus-specific Tc lymphocytes become active.Indeed,NK donot recogniz int ron al MHC cla which is produced by molecules:rather,they bind to other MHC class I-like d molecules and nonprotei molecules mmunity.All large anular lymphocytes (NK cells.y8 as may occu T cells and some CD+T cells)can be activated by the phosphor 然T THl-derived cytokine interleukin 2 L- 2)to exhibi themselves.When activated.T cells secrete evtokines ty:these are calle ymph LAK) particularly those that promote TH2 types of responses Dendritic Cells Natural Killer Cells Dendritic cells are so called because.when they are mature their cytoplasm extends into transient spiny dendrites and Ils and abou he veils. This provides a large surtac area for ther nta th Iymphocvtes.they have more cytopl sm and contai sing ten to a hundred times more antigen ntide prominent granules.In contrast to all T and B cells,NK MHCcomplexes than the other professional APCs(Bcells ive property of memory c iccelphags and y )rentiatinginto function is to kill infected cells and tumour cells using dendritic cells when stimulated by appropriate combina oughout the ENCYCLOPEDIA OF LIFE SCIENCES/e 2001 Nature Publishing Group /www.els.net presented on the cell surface. These cells then become targets for CD8+ TC cells with receptors specific for the viral peptides. Once the TC cells have bound to the infected cells, they have several mechanisms by which they can kill their targets. The TC cells secrete proteins stored in granules in their cytoplasm. These include perforins, which form pores through the surface membranes of the target cells, and granzymes, which enter the target cells through the perforin pores to activate caspase enzymes involved in apoptosis. TC cells also express a surface molecule called Fas ligand and a cytokine called tumour necrosis factor. These can induce apoptosis by binding to their respective receptors on target cells. In contrast to the limited expression of MHC class II molecules, most cells normally express MHC class I molecules and are thus potential targets for TC cells if they become infected or malignant. cd T lymphocytes The antigen receptors of some T cells are not made up of a and b chains, but comprise alternative polypeptides called g and d. These gd T cells constitute 10–15% of human blood T cells, but are abundant in epithelia of the gut, lungs and skin, where they appear to be important in immune responses to epithelial pathogens. Some mature in the thymus but others migrate directly from the bone marrow to the gut and mature there. The antigen receptors of gd T cells show much more limited diversity than those of ab T cells and do not recognize processed antigen peptides associated with conventional MHC class I and class II molecules: rather, they bind to other MHC class I-like molecules and nonprotein phosphorylated molecules expressed by cells undergoing stress, as may occur during infection. Indeed, some of the phosphorylated ligands recognized by gd T cells may be expressed by bacteria themselves. When activated, gd T cells secrete cytokines, particularly those that promote TH2 types of responses. Natural Killer Cells Natural killer (NK) cells constitute up to 15% of human blood lymphocytes. Together with gd T cells and about 50% of CD8+ T cells they are known as large granular lymphocytes because, compared with most T and B lymphocytes, they have more cytoplasm and contain prominent granules. In contrast to all T and B cells, NK cells do not express antigen-specific receptors and do not possess the adaptive property of memory cell development: they are therefore considered to form part of the innate immune system. However, like TC lymphocytes, their main function is to kill infected cells and tumour cells using similar mechanisms to those of TC cells to induce apoptosis of their targets. Since they lack antigen receptors, NK cells do not recognize specific antigens on the surface of a target cell. Instead, they detect molecular changes in the surface of a cell which are indicative of that cell being abnormal and therefore a potential threat to the body. In particular, they kill cells with reduced expression of MHC class I molecules, as can result from viral infection or malignant transformation. NK cells express surface ligands for MHC class I known as killer inhibitory receptors (KIRs) because their binding to MHC class I on the surface of a potential target cell inhibits the cytotoxic activity of the NK cell. This prevents NK cells from killing normal tissue cells with normal levels of MHC class I expression. However, when they interact with infected or malignant cells with reduced expression of MHC class I the lack of KIR engagement allows activation of the cytotoxic mechanisms. A variety of NK cell surface molecules can be involved in the interactions with targets cells which lead to killing, including CD2, CD16, CD69 and lectins (sugar-binding proteins). In addition, NK cells bear Fc receptors for IgG, so that killing can result from interaction with antibodies specifically bound to antigens on a target cell surface: this is called antibody-dependent cellular cytotoxicity (ADCC). Since they do not require activation by specific antigen in order to mediate their effects, NK cells are effective killers of infected cells during the early stages of a viral infection (thus demonstrating their ‘natural’ cytotoxicity) and help to limit the spread of the infection within the body until virus-specific TC lymphocytes become active. Indeed, NK cells are activated by interferon a, which is produced by virally infected cells, and are themselves a source of interferon g, which helps to promote cell-mediated immunity. All large granular lymphocytes (NK cells, gd T cells and some CD8+ T cells) can be activated by the TH1-derived cytokine interleukin 2 (IL-2) to exhibit enhanced antigen nonspecific cytotoxicity; these are called lymphokine-activated killer (LAK) cells. Dendritic Cells Dendritic cells are so called because, when they are mature, their cytoplasm extends into transient spiny dendrites and sheet-like veils. This provides a large surface area for their main function of antigen presentation to T lymphocytes. Indeed, they are the most potent APCs for T cells, expressing ten to a hundred times more antigen peptide– MHC complexes than the other professional APCs (B cells and monocyte/macrophages). All dendritic cells are derived from bone marrow stem cells, but appear to be heterogeneous, with various precursors (including monocytes) differentiating into dendritic cells when stimulated by appropriate combina￾tions of cytokines. Immature dendritic cells are found in tissues throughout the body (e.g. Langerhans cells in the Cells of the Immune System 4 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net