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SDF-1: the repulsive chemokine
IT July 2000
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Dendritic cells fired up on heat shock proteins
SDF-1: the repulsive chemokine 1 Mark C. Poznansky et al. (2000) Active movement of T cells away from a chemokine. Nat. Med. 6, 543–548 Chemokines set up concentration (or chemotactic) gradients in tissue, which influence target cells to migrate towards their source – ‘up’ concentration gradients. Poznansky and colleagues1 now provide the first report of a chemokine – stromal cell-derived factor-1 (SDF-1) – that is also able to stimulate the migration of cells away from its source: ‘down’ concentration gradients. In other words, SDF-1 can actively repel cells. SDF-1 attracts T cells, but the high concentrations of SDF-1 found in bone marrow and thymic stroma are not associated with the infiltration of large numbers of these cells. At concentrations of SDF-1 similar to those measured in bone marrow, the group measured selective repulsion of T-cell subpopulations [a response (termed ‘chemofugetaxis’) that could be distinguished from chemokinesis – the random movement of cells in the absence of a concentration gradient]. SDF-1 interacts with T cells solely through
the CXCR4 receptor, and blocking this receptor was found to inhibit both the attractive and repulsive activity of the chemokine. Blocking tyrosine kinases (which are involved in chemokine receptor-mediated signalling) with genistein and herbimycin inhibited movement towards SDF-1 but had little effect on movement away. Conversely, blocking cAMP (a signalling intermediate) suppressed movement away from the chemokine, but had no effect on movement towards it. Together, such results suggest that the same receptor–ligand interaction results in different signal-transduction pathways depending on the concentration of the ligand, SDF-1. The results raise the possibility that T-cell infiltration could be controlled by chemokine receptor stimulation. Whether similar mechanisms exist for other members of the structurally-related chemokine family remains to be seen. Bea Perks
Deconstructing the KIR–HLA complex 1 Boyington, J.C. et al. (2000) Crystal Structure of an NK cell immunoglobulin-like receptor in complex with its class I MHC ligand. Nature 405, 537–543 2 Tormo, J. et al. (2000) Crystal structure of a lectin-like natural killer receptor bound to its MHC class I ligand. Nature 402, 623–631 3 Natarajan, K. et al. (1999) Interaction of the NK cell inhibitory receptor Ly49A with H-2Dd: identification of a site distinct from the TCR site. Immunity 11, 591–601 When major histocompatibility complex (MHC) class I molecules present foreign peptides to cytotoxic CD81 T cells, the T cells are activated to kill the target cells. Natural killer (NK) cells also have receptors that interact with MHC class I molecules, but interaction with class I/self-peptides generates an inhibitory signal that prevents NK cell lysis of the target cell. Thus, NK cells do not kill normal, healthy class I-expressing cells, but do kill cells that express inadequate levels of class I, such as cancer cells. Inhibitory receptors on NK cells belong to two families – the immunoglobulin (Ig) superfamily (called killer inhibitory receptors, KIR), and the C-type lectin superfamily (called Ly49 receptors). Human inhibitory NK receptors can be of either type, whereas mice only have Ly49 receptors. Now, Boyington et al. report the first crystal structure of a KIR (KIR2DL2) in complex with its class I ligand (HLA-Cw3)1. The structure reveals that dimeric KIR binds across the top of the a1 and a2 helices of HLA-Cw3, and interacts with amino acids at positions 7 and 8 of the peptide. This interaction is similar to
that between the T-cell receptor (TCR) and MHC class I. However, the TCR binds centrally across the groove whereas the KIR binds at one end of the groove, with an area of overlap in-between. For NK T cells, this overlap suggests that it is unlikely that a TCR and a KIR on the same NK cell can simultaneously interact with a single MHC class I molecule. The KIR2DL2/HLA-Cw3 interaction is very different to the interaction between the murine dimeric receptor Ly49A and its class I ligand H-2Dd, which was described recently2,3. In this case, a single Ly49 molecule binds at one side of the peptide-binding groove. Although Ly49 does not interact directly with the peptide, the peptide must fill the groove for the Ly49A/H-2Dd interaction to occur. These studies provide the first structural information on the interaction between NK inhibitory receptors and MHC class I ligands. Further studies are required to address the role of zinc ions in KIR/HLA interactions, and to determine how KIR variants that induce NK cell lysis interact with class I molecules. Elaine Bell
1 Cho, B.K. et al. (2000) A proposed mechanism for the induction of cytotoxic T lymphocyte production by heat shock fusion proteins. Immunity 12, 263–272 Heat shock proteins (HSPs) have moved from relative obscurity in the field of immunology, to become an important family of immunogens. Although the main role of HSPs, such as HSP60, HSP70, HSP90 and gp96, appears to be as protein chaperones (contributing to protein folding, stability and transport), more recent studies have shown that injection of purified HSPs can prime cytotoxic T lymphocyte (CTL) immunity. Unlike most other proteins, HSPs do not require adjuvant to generate immunity and, unlike most other exogenous antigens, they can access the class I processing pathway. The isolation of HSPs from virus-infected or transformed cells to provide vaccines for generating anti-viral or anti-tumour CTL immunity has generated much interest. However, how HSPs perform their immunological function has remained unclear. In a significant step towards understanding the unique immunogenic properties of HSPs, Eisen and colleagues1 have examined the requirements for immunity to HSP65 fusion proteins. They show that HSP65 enables the processing of its fusion partner into the class I pathway of both macrophages and dendritic cells. Importantly, they show that such HSP fusion proteins could activate dendritic cells to become competent stimulators of naive CTLs without the need for CD41 T-cell help. Previous reports indicate that HSPs, such as human HSP60 and HSP70, can activate macrophages, but this is the first report of an HSP that activates dendritic cells. These findings might explain how HSPs generate CTL immunity in the absence of adjuvants. Whether other HSPs activate dendritic cells is unclear, but the fact that they are excellent immunogens and can activate macrophages, makes this likely. Interestingly, Eisen’s group excluded Toll-like receptor 4 as a target for HSP65, whereas Toll-like receptor 4 and CD14 have been implicated in signal transduction for other HSPs. Thus, different HSPs might have alternative ways of activating the innate immune system. Just how each HSP family exerts its immune functions will be of great interest. William R. Heath ([email protected])
J U L Y Vo l . 2 1
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14/6/00
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U P D AT E I M M U N O L O G Y TO D AY
Dendritic cells fired up on heat shock proteins
SDF-1: the repulsive chemokine 1 Mark C. Poznansky et al. (2000) Active movement of T cells away from a chemokine. Nat. Med. 6, 543–548 Chemokines set up concentration (or chemotactic) gradients in tissue, which influence target cells to migrate towards their source – ‘up’ concentration gradients. Poznansky and colleagues1 now provide the first report of a chemokine – stromal cell-derived factor-1 (SDF-1) – that is also able to stimulate the migration of cells away from its source: ‘down’ concentration gradients. In other words, SDF-1 can actively repel cells. SDF-1 attracts T cells, but the high concentrations of SDF-1 found in bone marrow and thymic stroma are not associated with the infiltration of large numbers of these cells. At concentrations of SDF-1 similar to those measured in bone marrow, the group measured selective repulsion of T-cell subpopulations [a response (termed ‘chemofugetaxis’) that could be distinguished from chemokinesis – the random movement of cells in the absence of a concentration gradient]. SDF-1 interacts with T cells solely through
the CXCR4 receptor, and blocking this receptor was found to inhibit both the attractive and repulsive activity of the chemokine. Blocking tyrosine kinases (which are involved in chemokine receptor-mediated signalling) with genistein and herbimycin inhibited movement towards SDF-1 but had little effect on movement away. Conversely, blocking cAMP (a signalling intermediate) suppressed movement away from the chemokine, but had no effect on movement towards it. Together, such results suggest that the same receptor–ligand interaction results in different signal-transduction pathways depending on the concentration of the ligand, SDF-1. The results raise the possibility that T-cell infiltration could be controlled by chemokine receptor stimulation. Whether similar mechanisms exist for other members of the structurally-related chemokine family remains to be seen. Bea Perks
Deconstructing the KIR–HLA complex 1 Boyington, J.C. et al. (2000) Crystal Structure of an NK cell immunoglobulin-like receptor in complex with its class I MHC ligand. Nature 405, 537–543 2 Tormo, J. et al. (2000) Crystal structure of a lectin-like natural killer receptor bound to its MHC class I ligand. Nature 402, 623–631 3 Natarajan, K. et al. (1999) Interaction of the NK cell inhibitory receptor Ly49A with H-2Dd: identification of a site distinct from the TCR site. Immunity 11, 591–601 When major histocompatibility complex (MHC) class I molecules present foreign peptides to cytotoxic CD81 T cells, the T cells are activated to kill the target cells. Natural killer (NK) cells also have receptors that interact with MHC class I molecules, but interaction with class I/self-peptides generates an inhibitory signal that prevents NK cell lysis of the target cell. Thus, NK cells do not kill normal, healthy class I-expressing cells, but do kill cells that express inadequate levels of class I, such as cancer cells. Inhibitory receptors on NK cells belong to two families – the immunoglobulin (Ig) superfamily (called killer inhibitory receptors, KIR), and the C-type lectin superfamily (called Ly49 receptors). Human inhibitory NK receptors can be of either type, whereas mice only have Ly49 receptors. Now, Boyington et al. report the first crystal structure of a KIR (KIR2DL2) in complex with its class I ligand (HLA-Cw3)1. The structure reveals that dimeric KIR binds across the top of the a1 and a2 helices of HLA-Cw3, and interacts with amino acids at positions 7 and 8 of the peptide. This interaction is similar to
that between the T-cell receptor (TCR) and MHC class I. However, the TCR binds centrally across the groove whereas the KIR binds at one end of the groove, with an area of overlap in-between. For NK T cells, this overlap suggests that it is unlikely that a TCR and a KIR on the same NK cell can simultaneously interact with a single MHC class I molecule. The KIR2DL2/HLA-Cw3 interaction is very different to the interaction between the murine dimeric receptor Ly49A and its class I ligand H-2Dd, which was described recently2,3. In this case, a single Ly49 molecule binds at one side of the peptide-binding groove. Although Ly49 does not interact directly with the peptide, the peptide must fill the groove for the Ly49A/H-2Dd interaction to occur. These studies provide the first structural information on the interaction between NK inhibitory receptors and MHC class I ligands. Further studies are required to address the role of zinc ions in KIR/HLA interactions, and to determine how KIR variants that induce NK cell lysis interact with class I molecules. Elaine Bell
1 Cho, B.K. et al. (2000) A proposed mechanism for the induction of cytotoxic T lymphocyte production by heat shock fusion proteins. Immunity 12, 263–272 Heat shock proteins (HSPs) have moved from relative obscurity in the field of immunology, to become an important family of immunogens. Although the main role of HSPs, such as HSP60, HSP70, HSP90 and gp96, appears to be as protein chaperones (contributing to protein folding, stability and transport), more recent studies have shown that injection of purified HSPs can prime cytotoxic T lymphocyte (CTL) immunity. Unlike most other proteins, HSPs do not require adjuvant to generate immunity and, unlike most other exogenous antigens, they can access the class I processing pathway. The isolation of HSPs from virus-infected or transformed cells to provide vaccines for generating anti-viral or anti-tumour CTL immunity has generated much interest. However, how HSPs perform their immunological function has remained unclear. In a significant step towards understanding the unique immunogenic properties of HSPs, Eisen and colleagues1 have examined the requirements for immunity to HSP65 fusion proteins. They show that HSP65 enables the processing of its fusion partner into the class I pathway of both macrophages and dendritic cells. Importantly, they show that such HSP fusion proteins could activate dendritic cells to become competent stimulators of naive CTLs without the need for CD41 T-cell help. Previous reports indicate that HSPs, such as human HSP60 and HSP70, can activate macrophages, but this is the first report of an HSP that activates dendritic cells. These findings might explain how HSPs generate CTL immunity in the absence of adjuvants. Whether other HSPs activate dendritic cells is unclear, but the fact that they are excellent immunogens and can activate macrophages, makes this likely. Interestingly, Eisen’s group excluded Toll-like receptor 4 as a target for HSP65, whereas Toll-like receptor 4 and CD14 have been implicated in signal transduction for other HSPs. Thus, different HSPs might have alternative ways of activating the innate immune system. Just how each HSP family exerts its immune functions will be of great interest. William R. Heath ([email protected])
J U L Y Vo l . 2 1
2 0 0 0 No.7
309