Antigen Recognition by Lymphocytes Antigen recognition by y T-cell receptors Natural Killer Cells Much of the antigen recognition byTcells,the natureof NK cells a nular lymphoc es which sent 5-14% any,are of peripheral blood mononuclear cells.They are effector proteins directly.without antigen proces sing and to (e.g.herpes),an (e.g.Lis recognize MHC molecules independently of bound pep etion (Trinchieri 1989)NK cells can utilize either antibody-dependent cell-mediated cells(Moritaetal.,1996).recognize cytotoxicity(ADCC)towards antibody-coa d target cells natura alterations of epithelial cells infected with any agent,such qually they eptor (KAR))and MHC class I-specific inhibitor elial cells infected Thes lized MHC (killer inhibitory receptor(KIR))receptors.Both receptors cass L-like molecules.which contain Bmicroglobulin ad re expressed differently on different subsets of NK cells heir hich prov ructures that can tory contr to cellular stress heat shock o Natural killer cell function the mouse one of these e molecules is H2-M3.which can N-terminal N-formylmethionine. NK uninfected inh this M IB-like the pre nce of IFNg.IFNB or IL-12. a monokine ated in the Qa-Tla region (e.g T18 duced early in many infections. IL-12 in synergism and can also be recognized byTcells.Anotherp tential with TNFa NK cells to produce arge s is the CDI molecule tha MHC sand pla n and early stage.For example,severe combined immunodefi- cient mice,which lack T and B cells,can resist infection with vay Biology of y T cells .cells uch as MatureTcells express many cell surface markers found These antibodies bind to FeRl on NK cells.which CD granzyme-dependent cyto vate ells ortant role in innat dependent on exogenous IL-2.During ontogeny of the lymphoid system,the Y6 T first mature I molecules,their function complements t CTLs as t they eliminate cells that ack MHO thymocytes.In the mouse.the v T cells are nfected with t have im found that aired MHC class expression. reas in hum they are also omm h hels that are Natural killer cell activating receptors ivated by m obacterial components strongly The main nk cell receptor involved in activating natural suggest a significant role in early protective immunity cytotoxicity is NKR-Pi.This receptor has the character- Sincey T cells utilize receptors encoded by st type C lectin and cognizes a wide mumty may b igands,espec However.depending on the state of activation and the activate (ea) ENCYCLOPEDIA OF LIFE SCIENCES/2001 Nature Publishing Group/www.els.net Antigen recognition by cd T-cell receptors Much of the antigen recognition by gd T cells, the nature of the antigens and the presenting molecules, if any, are far from fully elucidated. gd TCRs appear to recognize proteins directly, without antigen processing, and to recognize MHC molecules independently of bound pep￾tide. Moreover, small phosphate-containing nonpeptide compounds found in various microorganisms and para￾sites have also been identified as ligands for certain gd T cells (Morita et al., 1996). Conceivably gd T cells recognize alterations of epithelial cells infected with any agent, such as expression of stress or heat shock proteins. Equally they recognize MHC class IB molecules that are expressed when epithelial cells are infected. These are specialized MHC class I-like molecules, which contain b2-microglobulin and have a tissue-specific distribution. Their expression is under different regulatory control to MHC class I molecules, and in some cases they are induced in response to cellular stress (e.g. heat shock or certain infections). In the mouse, one of these molecules is H2-M3, which can present peptides with N-terminal N-formylmethionine, which is interesting because bacteria initiate protein synthesis with this residue. Other MHC class IB-like molecules are located in the Qa-Tla region (e.g T18) and can also be recognized by gd T cells. Another potential ligand for gd T cells is the CD1 molecule, the genes for which map outside the MHC region and which bind and present mycolic acid, a mycobacterial membrane component. Biology of cd T cells Mature gd T cells express many cell surface markers found on ab T cells. They differ in that they are almost exclusively CD4 2 and CD8 2 . When activated, gd T cells secrete the same cytokines as ab T cells, although most human clones secrete low levels of IL-2 and hence their growth is more dependent on exogenous IL-2. During ontogeny of the lymphoid system, the gd T cells are the first mature lymphocytes to appear during development of the embryo, at around day 14, thus before the development of ab thymocytes. In the mouse, the gd T cells are found predominantly in epithelium and less frequently in blood, whereas in humans they are also common in blood. The findings that gd T cells are preferentially located in epithelium, proliferate during infection and that some of them are activated by mycobacterial components strongly suggest a significant role in early protective immunity. Since gd T cells utilize receptors encoded by rearranging genes, this immunity may be seen as an interface between innate and adaptive immunity. Natural Killer Cells NK cells are granular lymphocytes which represent 5–14% of peripheral blood mononuclear cells. They are effector lymphocytes, contributing to early host defence against viral (e.g. herpes), and bacterial (e.g. Listeria monocyto￾genes) infections and lymphoid tumours by means of cytotoxicity and cytokine secretion (Trinchieri, 1989). NK cells can utilize either antibody-dependent cell-mediated cytotoxicity (ADCC) towards antibody-coated target cells or ‘natural’ cytotoxicity, which is regulated by a balance between ill-defined activating (i.e. killer cell activating receptor (KAR)) and MHC class I-specific inhibitory (killer inhibitory receptor (KIR)) receptors. Both receptors are expressed differently on different subsets of NK cells, which provides some variability in the structures that can be recognized by NK cells (Lanier, 1998). Natural killer cell function Although NK cells from uninfected organisms can kill sensitive targets, this activity is increased up to 100-fold in the presence of IFNa, IFNb or IL-12, a monokine produced early in many infections. IL-12 in synergism with TNFa also activates NK cells to produce large amounts of IFNg. This IFNg production precedes that by T cells and plays a crucial role in controlling infection at an early stage. For example, severe combined immunodefi- cient mice, which lack T and B cells, can resist infection with L. monocytogenes this way. ADCC by NK cells requires antibodies that bind cell￾associated antigens such as viral or bacterial proteins. These antibodies bind to FcgRIII on NK cells, which recognize mainly IgG1 and IgG3. The resulting cross￾linking of FcR elicits perforin–granzyme-dependent cyto￾toxicity, similar to CD8 1 CTLs. While NK cells play an important role in innate immunity, the fact that their KIRs recognize mainly MHC class I molecules, their function complements that of CD8 1 CTLs as they eliminate cells that lack MHC class I expression, such as certain tumour cells or cells infected with viruses that have impaired MHC class I expression. Natural killer cell activating receptors The main NK cell receptor involved in activating natural cytotoxicity is NKR-P1. This receptor has the character￾istics of a type C lectin and recognizes a wide variety of carbohydrate ligands, especially sulfated proteoglycans, constituents of the extracellular matrix of many cell types. However, depending on the state of activation and the availability of the relevant ligand on target cells, other molecules, such as CD2, b-integrins, CD44 and B7, can also activate NK cell killing (Renard et al., 1997). Antigen Recognition by Lymphocytes ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net 5