Dendritic cells fired up on heatshock proteins1 Cho, B.K. et al. (2000) A proposed mecha-nism for the induction of cytotoxic T lympho-cyte production by heat shock fusion proteins.Immunity 12, 263–272

Heat shock proteins (HSPs) have moved fromrelative obscurity in the field of immunology,to become an important family of immuno-gens. Although the main role of HSPs, such as HSP60, HSP70, HSP90 and gp96, appears to be as protein chaperones (contributing toprotein folding, stability and transport), morerecent studies have shown that injection of purified HSPs can prime cytotoxic T lympho-cyte (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 Iprocessing pathway. The isolation of HSPsfrom virus-infected or transformed cells toprovide vaccines for generating anti-viral oranti-tumour CTL immunity has generatedmuch interest. However, how HSPs performtheir immunological function has remainedunclear.

In a significant step towards under-standing the unique immunogenic propertiesof HSPs, Eisen and colleagues1 have examinedthe requirements for immunity to HSP65 fusion proteins. They show that HSP65 enables the processing of its fusion partnerinto the class I pathway of both macrophagesand dendritic cells. Importantly, they showthat such HSP fusion proteins could activatedendritic cells to become competent stimu-lators of naive CTLs without the need forCD41 T-cell help. Previous reports indicatethat HSPs, such as human HSP60 and HSP70, can activate macrophages, but this is the first report of an HSP that activates dendriticcells.

These findings might explain how HSPsgenerate CTL immunity in the absence of adjuvants. Whether other HSPs activate dendritic cells is unclear, but the fact that theyare excellent immunogens and can activatemacrophages, makes this likely. Interestingly,Eisen’s group excluded Toll-like receptor 4 asa target for HSP65, whereas Toll-like receptor4 and CD14 have been implicated in signaltransduction for other HSPs. Thus, differentHSPs might have alternative ways of activat-ing the innate immune system. Just how eachHSP family exerts its immune functions willbe of great interest.William R. Heath (Heath@wehi.edu.au)

Chemokines set up concentration (or chemo-tactic) 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 otherwords, SDF-1 can actively repel cells.

SDF-1 attracts T cells, but the high concen-trations of SDF-1 found in bone marrow andthymic stroma are not associated with the infiltration of large numbers of these cells. Atconcentrations of SDF-1 similar to those mea-sured in bone marrow, the group measuredselective repulsion of T-cell subpopulations [a response (termed ‘chemofugetaxis’) thatcould be distinguished from chemokinesis –the random movement of cells in the absenceof a concentration gradient].

SDF-1 interacts with T cells solely through

the CXCR4 receptor, and blocking this recep-tor was found to inhibit both the attractiveand repulsive activity of the chemokine.Blocking tyrosine kinases (which are involvedin chemokine receptor-mediated signalling)with genistein and herbimycin inhibitedmovement towards SDF-1 but had little effecton movement away. Conversely, blockingcAMP (a signalling intermediate) suppressedmovement away from the chemokine, buthad no effect on movement towards it. To-gether, such results suggest that the same receptor–ligand interaction results in differentsignal-transduction pathways depending onthe concentration of the ligand, SDF-1.

The results raise the possibility that T-cellinfiltration could be controlled by chemokinereceptor stimulation. Whether similar mecha-nisms exist for other members of the struc-turally-related chemokine family remains tobe seen.Bea Perks

When major histocompatibility complex(MHC) class I molecules present foreign pep-tides to cytotoxic CD81 T cells, the T cells areactivated to kill the target cells. Natural killer(NK) cells also have receptors that interactwith MHC class I molecules, but interactionwith class I/self-peptides generates an in-hibitory signal that prevents NK cell lysis ofthe target cell. Thus, NK cells do not kill normal, healthy class I-expressing cells, butdo kill cells that express inadequate levels ofclass I, such as cancer cells. Inhibitory receptorson NK cells belong to two families – the im-munoglobulin (Ig) superfamily (called killerinhibitory receptors, KIR), and the C-type lectinsuperfamily (called Ly49 receptors). Humaninhibitory NK receptors can be of either type,whereas mice only have Ly49 receptors.

Now, Boyington et al. report the first crys-tal structure of a KIR (KIR2DL2) in complexwith its class I ligand (HLA-Cw3)1. The struc-ture reveals that dimeric KIR binds across thetop of the a1 and a2 helices of HLA-Cw3, andinteracts with amino acids at positions 7 and 8of the peptide. This interaction is similar to

that between the T-cell receptor (TCR) andMHC class I. However, the TCR binds cen-trally across the groove whereas the KIRbinds at one end of the groove, with an area ofoverlap in-between. For NK T cells, this over-lap suggests that it is unlikely that a TCR anda KIR on the same NK cell can simultaneouslyinteract with a single MHC class I molecule.

The KIR2DL2/HLA-Cw3 interaction isvery different to the interaction between themurine dimeric receptor Ly49A and its class Iligand H-2Dd, which was described recently2,3.In this case, a single Ly49 molecule binds atone side of the peptide-binding groove. Al-though Ly49 does not interact directly withthe peptide, the peptide must fill the groovefor the Ly49A/H-2Dd interaction to occur.

These studies provide the first structuralinformation on the interaction between NKinhibitory receptors and MHC class I ligands.Further studies are required to address therole of zinc ions in KIR/HLA interactions, andto determine how KIR variants that induce NKcell lysis interact with class I molecules.Elaine Bell

U P D A T EI M M U N O L O G Y TO D AY

V o l . 2 1 N o . 7 3 0 9

J U L Y 2 0 0 0

Deconstructing the KIR–HLA complex1 Boyington, J.C. et al. (2000) Crystal Structure of an NK cell immunoglobulin-like receptor incomplex with its class I MHC ligand. Nature 405, 537–5432 Tormo, J. et al. (2000) Crystal structure of a lectin-like natural killer receptor bound to itsMHC class I ligand. Nature 402, 623–6313 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

SDF-1: the repulsive chemokine1 Mark C. Poznansky et al. (2000) Active movement of T cells away from a chemokine. Nat.Med. 6, 543–548

IT July 2000 14/6/00 9:16 am Page 309