475

A selection of interesting papers that were published inthe two months before our press date in major journalsmost likely to report significant results in immunology.

Current Opinion in Immunology 1999, 11:475–483

Contents (chosen by)475 Antigen recognition (Elliott)476 Innate immunity (Bonneville)477 Lymphocyte development (Kruisbeek)477 Immunological techniques (Liu)478 Lymphocyte activation and effector functions (Ono and

Radosevich)479 Immunity to infection (Bonneville)479 HIV (Rowland-Jones)480 Genetic effects on immunity (Casanova)480 Cancer (Walker)481 Transplantation (Wood and Bushell)482 Atopic allergy and other hypersensitivities (Ono and

Radosevich)482 Autoimmunity (Bonneville)

• of special interest•• of outstanding interest

Antigen recognition Selected by Tim ElliottJohn Radcliffe Hospital, Oxford, UK

CD40 activation in vivo overcomes peptide-induced periph-eral cytotoxic T-lymphocyte tolerance and augmentsanti-tumor vaccine efficacy. Diehlt L, Th den Boert A,Schoenberger SP, van der Voort EIH, Schumacher TNM, MeliefCJM, Offringa R, Toes REM: Nat Med 1999, 5:774-779.

ANDConversion of tumor-specific CD4+ T-cell tolerance to T-cellpriming through in vivo ligation of CD40. Sotomayor EM,Borrello l, Tubb E, Rattis F-M, Bien H, Lu Z, Fein S,Schoenberger S, Levitsky HI: Nat Med 1999, 5:780-787.•• Significance: The presentation of antigens to naive T cells inthe absence of appropriate costimulation often leads to toler-ance induction. One essential component of costimulation isthe expression of CD40 by the antigen-presenting cell — mosttypically an activated dendritic cell. Therefore, antigens pre-sented by non-haematopoetic tumour cells or preprocessedpeptide antigens presented by nonactivated antigen-presentingcells frequently lead to antigen-specific tolerance. Such is thecase for some experimental tumours and for peptide vaccinesadministered in ‘nonactivating’ adjuvants. These two papersshow how such tolerogenic stimuli can be overcome by theaddition of anti-CD40 antibodies. Such antibodies may find aplace as ‘intelligent adjuvants’ in vaccination against tumoursand infectious organisms.Findings: The paper by Diehlt et al. deals with a tumour modelinvolving protective CTLs whereas Sotomayor et al. describe asystem involving antitumour CD4+ T cells although it is notclear from this study whether these play a regulatory or aneffector role in antitumour immunity. In the paper by Diehlt etal., the tolerogenic effect of a peptide vaccine against anexperimental tumour (which expresses murine CD80 and highlevels of the tumour-specific peptide epitope) was overcome

by the in vivo administration of an agonist anti-CD40 antibodyinjected at the time of the peptide vaccine. This resulted in alevel of tumour immunity that was considerably higher than thatseen when the tumour was implanted in the absence of anti-body. In the paper by Sotomayor et al., CD4+ T cell tolerancewas observed when an experimental tumour (aRENalCArcinoma expressing a model antigen) is implantedinto a mouse transgenic for a TCR specific for the model anti-gen. Tolerance could be alleviated by the administration ofanti-CD40 monoclonal antibody. This was measured by therestoration of a Th1 response to recombinant vacciniaexpressing the model antigen and also by a slight increase inpriming against the tumour in the absence of vaccination. Thistranslated into corresponding levels of antitumour immunitywhen lung metastases were scored. As for the tumour-specif-ic peptide epitope in the Diehlt study, the model peptideantigen is also tolerogenic but can be made immunogenic bythe administration of anti-CD40. In contrast to the tumourmodel this resulted in an IL-4 secreting, TH2 response.

The specificity of a weak γγδδ TCR interaction can be modu-lated by the glycosylation of the ligand. Hampl J, Schild H,Litzenberger C, Baron M, Crowley MP, Chien Y: J Immunol1999, 163:288-294. •• Significance: T cells bearing nonclassical γδ receptors arethought to contribute to immunity by providing a first-linedefence against damaged or infected cells. Some recogniseclassical MHC molecules, others recognise nonclassical orMHC-like molecules and recognition does not appear todepend on a bound peptide ligand. This study shows that thismay result in a lower-affinity interaction with target cells, whichis sensitive to changes in MHC glycosylation. Altered post-translational modification in cells is often an early response toenvironmental assault and would be an appropriate signal for γδT cell recruitment. Although the γδ cells in this study are inhib-ited by these changes, it is conceivable that recognition byother γδ T cells of such altered-self-MHC could be augmented.Findings: A γδ T cell clone which recognises H2-IEk wasshown to have a lower affinity for its ligand than IEk-restrictedαβ T cell clones on the basis of its lack of staining with fluores-cent, tetrameric IEk and its dependence on high-density,immobilised IEk for activation. The region of the IEk moleculerecognised by the clone was mapped to residues 67, 70 and71. Mutations at position 79 also inhibited recognition byaffecting the glycosylation of position 82 of the IEk α chain. IEk

with no glycosylation site at position 82 was, however, stimula-tory. Isoelectric focusing of nonstimulatory IEk (including theposition 79 mutant, as well as IEk expressed in the human cellline 721.134 and the mutant CHO cell line End-4) indicated theloss of more negatively charged bands from the α-chain spec-trotype. Together, these data suggest that recognition by the γδT cell was sensitive to hyposialylation of the glycan at position82 of the IEk α chain.

The selective downregulation of class I major histocompat-ibility complex proteins by HIV-1 protects HIV-infected cellsfrom NK cells. Cohen GB, Gandhi RT, Davis DM, MandelboimO, Chen BK, Strominger JL, Baltimore D: Immunity 1999,10:661-671.

ImmunologyPaper alert

imb5pap.qxd 10/14/1999 8:58 AM Page 475

•••• Significance: Viruses avoid detection by cytotoxic T lympho-cytes (CTLs) in many ways. The nef protein of HIV-1 increasesthe rate of endocytosis of MHC class I molecules. This studyshows that this is true for HLA-A and -B but not HLA-C or -E.Since HLA-C (like HLA-E) was shown to act as a ligand for nat-ural killer (NK) cell inhibitory receptors, it is possible that HIV-1could escape detection by CTLs by downregulating classicalMHC class I molecules while remaining protected from NK cellkilling (that would result from such downregulation) by sparingthe NK-cell-inhibitory class I molecules from the same fate.Findings: Infection with HIV-1 of the human B cell line 721.220transfected with different HLA molecules showed that HLA-A2and -B2705 but not -Cw4 or the class-I-like molecule CD1dwere downregulated. This phenomenon mapped to residuesTyr321, Asp328 and Ala325 in the cytoplasmic domain of theclass I molecule. The HLA-E cytoplasmic tail (which has Tyr321and Asp328 but Glu at position 325) protected HLA-A2 fromnef-mediated downregulation when a chimeric molecule wasstudied. In addition to confirming that HLA-E expression con-fers protection against NK cells with the CD94–NKG2Areceptor, this group showed that HLA-Cw4 expression pro-tected against NK cells expressing the NK inhibitory receptorR1 (NKIR1).

Pathogen subversion of cellular immunity: Immunol Rev1999, 168:1-255. •• Significance: An up-to-date and comprehensive series ofreviews.Findings: Many pathogens need to gain access to their host’sintracellular space in order to propagate. In doing so, they riskdetection by the specific immune system. Among micro-organ-isms, many mechanisms have evolved to counter immunologicaldisclosure or eradication. This volume of ImmunologicalReviews illustrates how the necessity to survive in an immuno-logically hostile host really is the mother of evolutionaryinvention. Examples are taken from SV40, lentiviruses, measlesvirus, HIV-1, adenovirus, myxoma virus, papillomavirus, varicellazoster, cytomegalovirus and murine mammary tumour virus aswell as bacteria such as Yersinia and Salmonella. Mechanismsinclude evasion from recognition by class-I-restricted T cells,class-II-restricted T cells and NK cells; there are reviews onimmunosupression of an antiviral response and mimics ofchemokine receptors and cytokines.

Retrograde protein translocation: ERADication of secretoryproteins in health and disease. Plemper RK, Wlolf DH:Trends Biochem Sci 1999, 24:266-270. •• Significance: An up-to-date and comprehensive review.Findings: Molecular immunologists are interested in retro-grade protein translocation for a number of reasons. It is oneroute by which MHC class I molecules are catabolised — aprocess that is accelerated by proteins encoded by humancytomegalovirus — and it is the pathway that is subverted byHIV-1 for the downregulation of CD4. Both these are potentialimmune-evasion mechanisms. It is also the degradation path-way followed by some glycoproteins that are processed forpresentation to cytotoxic T lymphocytes by MHC class I mole-cules. This review puts these interesting immunologicalphenomena in the context of a fascinating and newly discov-ered biochemical mechanism.

Innate immunity Selected by Marc BonnevilleINSERM U 463, Institut de Biologie, Nantes, France

The nature of the principal type 1 interferon-producing cellsin human blood. Siegal FP, Kadowaki N, Shodell M, Fitzgerald-Bocarsly PA, Shah K, Ho S, Antonenko S, Lui YJ: Science1999, 284:1835-1837.

ANDPlasmacytoid monocytes migrate to inflamed lymph nodesand produce large amounts of type I interferon. Cella M,Jarrossay D, Facchetti F, Alebardi O, Nakajima H,Lanzavecchia A, Colonna M: Nat Med 1999, 8:919-923.•• Significance: These two studies describe the isolation ofthe long-sought ‘natural’ interferon-producing cells and reveal anovel dual function of dendritic cells (DCs) in innate and adap-tive immunity.Findings: Plasmacytoid monocytes, a rare cell type defined bya plasma-cell-like morphology and by expression of CD4 butlack of lineage markers, can give rise to type 2 dendritic cells, asubset of DCs promoting differentiation of type 2 Th cells.Plasmacytoid monocytes are shown here to produce largeamounts of interferon α, a cytokine with major antiviral and anti-tumour properties and pleiotropic effects on innate immunecells, when exposed to inactivated herpes simplex virus (Siegalet al.) or influenza virus (Cella et al.).

HMG-1 as a late mediator of endotoxin lethality in mice.Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M,Che J, Frazier A, Yang H, Ivanova S, Borovikova L et al.:Science 1999, 285:248-251.• Significance: This study identifies a late mediator of endotox-emia, which could be a convenient marker of disease severityand a potential target for therapeutic intervention.Findings: Endotoxin (lipopolysaccharide), a component ofGram-negative bacteria, stimulates rapid release bymacrophages of large amounts of tumour necrosis factor (TNF)and IL-1, two early mediators of lethal endotoxemia. This studyidentifies high mobility group 1 protein (HMG-1) as a potentiallate mediator of endotoxemia for four reasons: first, HMG-1 isreleased in vitro by macrophages several hours after simulationwith endotoxin, TNF or IL-1; second, antibodies to HMG-1attenuate endotoxin-mediated lethality in mice; third, adminis-tration of HMG-1 is lethal; fourth, increased serum levels ofHMG-1 are found in mice up to 32 hours after endotoxin expo-sure as well as in septic patients who succumbed to infection.

Activation of NK cells and T cells by NKG2D, a receptor forstress-inducible MICA. Bauer S, Groh V, Wu J, Steinle A,Phillips JH, Lanier LL, Spies T: Science 1999, 285:727-729. •• Significance: This study describes a novel receptor,expressed by NK cells and a large fraction of T cells, that rec-ognizes stress-inducible ligands upregulated on epithelialtumors and which may therefore promote antitumor naturalkillers (NK) and T cell responses.Findings: MICA, a distant homolog of MHC class I molecules,is induced on stressed intestinal epithelium and is frequentlyexpressed in epithelial tumors. This study describes a receptorfor MICA; the receptor is present on NK cells, γδ T cells andCD8+ αβ T cells and is identified as NKG2D — an orphanlectin-like receptor. Cross-linking of NKG2D by specific mono-clonal antibodies activates cytotoxic activity of γδ and NK cellsand masking of NKG2D inhibits γδ T cell recognition of trans-fectants and tumors expressing MICA. Hence NKG2D is a

476 Paper alert

imb5pap.qxd 10/14/1999 8:58 AM Page 476

novel immunoreceptor that activates/potentiates antitumor NKand T cell responses.

Host defense mechanisms triggered by microbial lipopro-teins through Toll-like receptors. Brightbill HS, Libraty DH,Krutzik SR, Yang RB, Belisle JT, Bleharski JR, Maitland M,Norgard MV, Plevy SE, Smale ST et al.: Science 1999,285:732-736.

ANDCell activation and apoptosis by bacterial lipoproteinsthrough Toll-like receptor-2. Aliprantis AO, Yang RB, MarkMR, Suggett S, Devaux B, Radolf JD, Klimpel GR, Godowski P,Zychlinsky A: Science 1999, 285:736-739. •• Significance: These studies provide a molecular basis forthe adjuvant activity of bacterial lipoproteins and demonstrate akey role of Toll-like receptors in initiating innate defense mech-anisms against infections pathogens.Findings: Bacterial lipoproteins (BLP), which are produced byboth Gram+ and Gram– bacteria, are known to activate innateimmune responses through yet-undefined mechanisms.Brightbill et al. show that BLP stimulate IL-12 and nitric oxideproduction by human macrophages through human Toll-likereceptor-2 (hTLR2). Aliprantis et al. Show that BLP not onlyactivate phagocyte respiratory burst but also induce cell apop-tosis through hTLR2. Thus hTLR2 represents a molecular linkbetween apoptosis and innate immune cell activation, twomechanisms implicated in the generation and resolution ofinflammation in response to bacterial pathogens.

Lymphocyte development Selected by Ada KruisbeekThe Netherlands Cancer Institute, Amsterdam, The Netherlands

Coordinate regulation of B cell differentiation by the tran-scription factors EBF and E2A. O’Riordan M, Grosschedl R:Immunity 1999, 11:21-31. •• Significance: Cell fate decisions in the B cell lineage areaffected by a number of transcription factors that appear toquite specifically regulate early B cell development. These tran-scriptional regulators include EBF (early B cell factor), E2A andBSAP (Pax5). Ebf–/– and E2a–/– mice have a similar pheno-type — a severe defect in early B cell development, prior to theinitiation of immunoglobulin-gene rearrangements. Here, thepossibility of a molecular collaboration between EBF and E2Ais investigated.Findings: Mice heterozygous for mutations in both Ebf and E2ahave a greater reduction in their numbers of pro-B cells thansingle-heterozygous littermate controls. Differentiation withinthe pro-B-cell compartment is also more severely disturbed indouble (compared with single) heterozygous mutant mice andexpression of a number of genes known or suspected to regu-late B cell development (Pax5, Rag1, Rag2 and mb-1) issignificantly reduced in Ebf+/–E2a+/– double-heterozygousfetal liver samples, compared with controls that are single het-erozygotes for Ebf or E2a. Together, these data suggest thatEBF and E2A act co-ordinately in B cell development and thisnotion is corroborated by the observation that EBF and E2Acan form a ternary complex at a target promotor. Temporal pat-terns of gene activation in B cell development are thusregulated by transcriptional synergy.

Inherited human Caspase 10 mutations underlie defectivelymphocyte and dendritic cell apoptosis in autoimmunelymphoproliferative syndrome type II. Wang J, Zheng L,

Lobito A, Chan FK-M, Dale J, Sneller M, Yao X, Puck JM, StrausSE, Lenardo MJ: Cell 1999, 98:47-58. •• Significance: Patients with autoimmune lymphoproliferativesyndrome (ALPS) manifest an accumulation of lymphocytesand autoimmune disorders and this syndrome has been identi-fied as an inherited disease of lymphocyte homeostasis anddefective Fas-mediated apoptosis. Unraveling the molecularbasis for this disease may be key to a better understanding ofthe regulation of homeostasis in the immune system and it wasof interest that a number of ALPS patients did not exhibit muta-tions in Fas or FasL (Fas ligand). The present study set out toexamine which other components of death-receptor pathwaysmight be defective in this subgroup (ALPS type II) of patients.Findings: Two separate ALPS-type-II families were found tohave inherited mutations in Caspase 10 and not in other death-receptor-related genes such as those for TNF receptors 1 or 2,Caspase 8, FADD, Fas or FasL. The Caspase 10 mutationsresulted in decreased Caspase activity and interference withFasL- and TRAIL-induced apoptosis. Remarkably, one of thepatients exhibited not only T and B cell accumulation but alsodisturbed homeostasis of the dendritic cell lineage; a markedaccumulation of dendritic cells was found in the T cell areas ofthe lymph nodes. Given the autoimmune pathology observed inthese patients, it will be of interest to dissect which of thedefects (in T cell or dendritic cell apoptosis) is instrumental indisturbing negative selection in the thymus and the periphery.

Positive selection of natural autoreactive B cells. HayakamaK, Asano M, Shinton SA, Gui M, Allman D, Stewart CL, Silver J,Hardy RR: Science 1999, 285:113-116. •••• Significance: In both T and B lymphocytes, antigen-recep-tors have a dual function: these receptors are involved in ligandrecognition late in the lifespan of T and B cells and they controldevelopment at an earlier stage. Dependent on the affinity/avid-ity of their antigen-receptor for self-MHC–peptide complexes,T cells are either positively or negatively selected. While B cellscan also be negatively selected by interactions with self anti-gens, it has been less clear whether there is any positive rolefor self-reactivity in the B cell compartment. The present studyaddresses this issue, by following the fate of naturally generat-ed autoreactive B cells in a murine model system.Findings: Using mice with a germline-gene-encoded antigen-receptor specificity for a naturally occurring self antigen, it isshown that self antigen promotes B cell accumulation andserum autoantibody secretion. Self antigens can therefore pos-itively affect B cell fate. These findings perhaps also explain theearlier observation (KP Lam, R Kuhn, K Rajewsky: In vivo abla-tion of surface immunoglobulin on mature B inducible cells bygene targeting results in rapid cell death. Cell 1997, 90:1073-1083.) that a certain degree of signaling through the B cellreceptor is important in B cell maintenance.

Immunological techniques Selected by Yang LiuOhio State University, Columbus, Ohio, USA

Presentation of out-of-frame peptide/MHC class I com-plexes by a novel translation initiation mechanism.Malarkannan S, Horng T, Shih PP, Schwab S, Shastri N:Immunity 1999, 10:681-690. •• Significance: An elegant analysis that combines a sensitiveT cell activation assay, peptide analysis and gene transfer toestablish nonconventional translation initiation and the codingof the first codon. The conclusion of the study has important

Paper alert 477

imb5pap.qxd 10/14/1999 8:58 AM Page 477

implications for both the diversification and the nature of anti-genic peptides presented by MHC class I.Findings: Peptide presented by MHC class I can be encod-ed by an alternative translational reading frame that usesCUG rather than AUG; the CUG is decoded as leucine ratherthan methionine.

The immunological synapse: a molecular machine control-ling T cell activation. Grakoui A, Bromley SK, Sumen C, DavisMM, Shaw AS, Allen PM, Dustin ML: Science 1999285:221-227. •••• Significance: This is the first real-time imagine and quanti-tative analysis of the formation of a functional immunologicalsynapse between T cells and a planar membrane containingboth an antigenic peptide and an adhesion molecule, ICAM-1.The study provides a much-needed molecular depiction of theearly events in T cell activation.Findings: The immunological synapse formation can be dividedinto three stages: junction formation, MHC–peptide trans-portation and stabilization. The transportation stage can act onligands with distinctive kinetics whereas stabilization of theMHC–peptide complex at the center of the synapse is a deter-minative event for T cell proliferation.

Lymphocyte activation and effector functions Selected by Santa Ono and Michael RodosevichHarvard Medical School, Boston, Massachusetts, USA

Biochemical association of CD45 with the T cell receptorcomplex: regulation by CD45 isoform and during T cell acti-vation. Leitenberg D, Boutin Y, Lu D, Bottomly K: Immunity1999, 10:701-711.•• Significance: CD45 is a transmembrane tyrosine phos-phatase that is composed of a large extracellular domain,which can exist in several different isoforms generated by alter-native RNA spicing, and a cytoplasmic domain with proteintyrosine phosphatase activity that is required for efficient TCRsignal transduction. In CD4+ T cells, the expression of differ-ent isoforms of CD45 is regulated during the generation andmaturation of an immune response and also in different effec-tor cell subsets. This regulated pattern of different isoformexpression suggests that the ectodomain of CD45 may influ-ence the activity of the cytoplasmic domains, which areinvolved in phosphorylation.Findings: The authors demonstrated a basal biochemicalassociation of CD45 with the TCR complex that is partiallyregulated by the expression of different CD45 isoforms. Inaddition, it was shown that maintenance of CD45–TCR asso-ciation is differently regulated following TCR ligation withpeptide. An agonistic peptide promotes sustained associationin a CD4-dependent manner whereas a partially agonistic pep-tide induces CD45–TCR dissociation. The data provideevidence that association of the CD45 with the TCR is likely tobe an important regulatory mechanism both before and duringT cell activation.

TCRααββ-independent CD28 signaling and costimulationrequire non-CD4-associated Lck. Leung BL, Haughn L,Veillette A, Hawley RG, Rottapel R, Julius M: J Immunol 1999,163:1334-1341.• Significance: Two signals, one from the TCR and a secondthrough CD28, are required for optimal T cell activation. Thispaper investigates signal transduction processes fromCD28. Specifically, it addresses the controversial issue of

whether src-family protein tyrosine kinases are involved inCD28 signal transduction. Findings: The investigators used monoclonal antibodies direct-ed to CD28 to study signal transduction in primary resting Tcells. A series of murine T cell clonal variants were also studied,as they are particularly amenable to Lck-dependent signaltransduction. The investigators demonstrate that CD4–, but notCD4+, clonal variants respond to CD28-specific monoclonalantibodies. This implies that non-CD4-associated Lck can func-tionally limit CD28-mediated signalling.

Th cells and Th2 responses can develop in the absence ofMHC class II-CD4 interactions. Wack A, Corbella P, Harker N,Roderick K, Norton T, Williams K, Williams O, Kiossis D:J Immunol 1999, 163:1162-1169.• Significance: Th cells are CD4+ and class-II-restricted. Thishas suggested that differentiation programs controlling func-tional commitment, MHC restriction and co-receptorexpression are co-ordinated. However, whether this co-ordinatedifferentiation process is a requirement for the generation of Thsubsets has not been formally proven. Using mice doubly trans-genic for CD8 and the class-I-restricted TCR F5, theseinvestigators tested whether interactions between CD4 andclass II are necessary for thymic differentiation of mature CD4+

T cells and whether commitment to Th1 or Th2 subsets is influ-enced by class II or CD4 molecules. Findings: Remarkably, neither class II nor CD4 expression wasnecessary for the generation and helper function of transgenicT cells. Thus, the canonical combinations of co-receptor andfunction do not determine functional commitment.

Structure of a heterophilic adhesion complex between thehuman CD2 and CD58 (LFA-3) counterreceptors. Wang J-H,Smolyar A, Tan K, Liu J-H, Kim M, Zhen-Yu JS, Wagner G,Reinherz EL: Cell 1999, 97:791-803.•• Significance: During lymphocyte activation, interactionsbetween T cells or natural killer cells and antigen-presentingcells precede TCR–MHC recognition. This relatively low-affinity interaction is facilitated by contacts between CD2 andLFA-3. This paper describes the crystal structure of the het-erophilic adhesion complex between the amino termini of thesetwo polypeptides.Findings: Remarkably, the interaction surface between CD2and LFA-3 is strikingly asymmetric. The interaction involves themajor β sheets of the two immunoglobulin-like domains andthere is poor shape complementarity. There are virtually nohydrophobic forces and the complex is held together by hydro-gen bonds and salt bridges. Thus, the structure provides insightto the high specificity but low affinity of interaction betweenthese two molecules.

Activation of NK cells and T cells by NKG2D, a receptor forstress-inducible MICA. Bauer S, Groh V, Wu J, Steinle A,Phillips JH, Lanier LL, Spies T: Science 1999, 285:727-730.•• Significance: The regulation of antitumor activity by natur-al killer (NK) cells and T cells involves both inhibitory signalsand less-well-characterized activating signals. Inhibitory sig-nals are delivered by the NKG2A or NKG2C receptors whichinteract with the HLA-A, -B or -C molecules. The authors haveidentified the MICA and MICB class-I-related molecules asboth a stress-inducible antigen and an activating structure ontumor cells. This paper reports the identification of a receptorfor MICA.

478 Paper alert

imb5pap.qxd 10/14/1999 8:58 AM Page 478

Findings: Using representational difference analysis, the inves-tigators identify a receptor for MICA to be NKG2D, an orphanC-type-lectin-like NK cell receptor of previously unknownexpression and function. The receptor is expressed on allappropriate γδ T cells as well as CD8+ αβ T cells and NK cells.Ligation of NKG2D activates cytolytic responses of γδ T cellsand NK cells against transfectants expressing MICA.

Pre-TCR signaling and inactivation of p53 induces crucialcell survival pathways in pre-T cells. Haks MC, Krimpenfort P,van den Brakel J, Kruisbeek AM: Immunity 1999, 11:91-101.• Significance: Signaling through the pre-TCR is required forintrathymic T cell differentiation from the double-negative tothe double-positive stage. CD3γ is essential for this signal-transduction process. Mice deficient in CD3γ exhibit aprofound increase in the number of apoptotic double-nega-tive thymocytes. This paper uncovers a downstream target ofthe pre-TCR which regulates the transition into the double-positive stage. Findings: Introduction of p53 deficiency into the background ofthe CD3γ-deficient mice rescued the block in thymocyte differ-entiation. The number of double-positive thymocytes is restoredto normal. Thus pre-TCR signaling appears to inactivate p53during the survival and differentiation of pre-T cells.

Immunity to infection Selected by Marc BonnevilleINSERM U 463, Institut de Biologie, Nantes, France

Plasmodium falciparum-infected erythrocytes modulate thematuration of dendritic cells. Urban BC, Ferguson DJP,Pain A, Willcox N, Plebanski M, Austyn JM, Roberts DJ: Nature1999, 400:73-77.• Significance: These data demonstrate a novel mechanism bywhich malaria parasites induce immune dysregulation and pro-vide an explanation for the clinical and experimental evidence ofimmune suppression often seen during malaria infection.Findings: It is shown here that intact P.-falciparum-infected ery-throcytes adhere to dendritic cells (DCs), inhibit maturation ofDCs and suppress their subsequent ability to activate primaryand secondary T cell immune responses against malarial andother antigens.

Therapy of tuberculosis in mice by DNA vaccination. LowrieDB, Tascon RE, Bonato VLD, Lima VMF, Faccioli LH,Stavropoulos E, Colston MJ, Hewinson RG, Moelling K, SilvaCL: Nature 1999, 400:269-271. •• Significance: This study provides the first demonstrationthat DNA vaccines can have a pronounced therapeutic actionon Mycobacterium tuberculosis infection in rodents and thuscould be a valuable adjunct to conventional antibacterial drugsto treat human tuberculosis.Findings: The therapeutic effect of DNA vaccines was studiedin mice with an established (8 week) infection with a virulentstrain of M. tuberculosis. Mice were given plasmid DNAexpressing either mycobacterial heat-shock protein 65(Hsp65) or murine IL-12, a cytokine that plays a crucial role inthe development of protective immunity against tuberculosis.Either treatment resulted in rapid decline of live bacteria inspleen and lungs and was associated with a switch from a pre-dominantly Th2 to a predominantly Th1 (proinflammatory)T cell response. When given after chemotherapy, injection ofHsp65 DNA also allowed elimination of residual bacteria froma large proportion of mice.

HIV Selected by Sarah Rowland-JonesJohn Radcliffe Hospital, Oxford, UK

The selective downregulation of class I major histocompat-ibility complex proteins by HIV-1 protects HIV-infected cellsfrom NK cells. Cohen GB, Gandhi RT, Davis DM,Mandelboim O, Chen BK, Strominger JL, Baltimore D:Immunity 1999, 10:661-671. •••• Significance: The complexity of the mechanisms employedby HIV to evade the host immune response is underscored bythis report, which shows that the virus selectively downregu-lates HLA class I A and B molecules on infected cells, whilstleaving HLA-C expression unchanged in order to avoid naturalkiller (NK) cell recognitionFindings: This group previously demonstrated that HIV-infected cells show significantly reduced expression ofclass I molecules, which makes them poor targets for HIV-specific cytotoxic T lymphocytes (CTLs). Using HIV deletionmutants, the activity was mapped to the nef gene. This studyemployed transfected 221 cells infected with HIV to showthat downregulation of class I is selective for A and B mole-cules whilst expression of HLA-C and -E is unaffected,thereby rendering the infected cells resistant to NK-cell-mediated lysis. Chimeric class I molecules were thenconstructed and used to map the critical regions of the intra-cytoplasmic domain of class I molecules for the interactionwith HIV nef. Thus HIV is able to avoid not only the dominantHIV-specific CTL responses that are restricted by class I Aand B molecules but also NK responses, which are inhibitedby expression of HLA-C and -E. However, it does imply thatHLA-C-restricted CTL responses may be of particular valueto the HIV-infected host.

Effect of interleukin-2 on the pool of latently infected, rest-ing CD4+ T cells in HIV-1-infected patients receiving highlyactive anti-retroviral therapy. Chun TW, Engel D, Mizell SB,Hallahan CW, Fischette M, Park S, Davey RT Jr, Dybul M,Kovacs JA, Metcalf JA et al.: Nat Med 1999, 5:651-655. •• Significance: IL-2 therapy used in conjunction with HAARTappears to reduce the residual pool of latently infected CD4+ Tcells.Findings: A series of reports that were highlighted in the lastHIV ‘Paper alert’ showed that even in HAART-treated patientswith optimal suppression of their plasma viral load, a pool oflatently infected resting CD4+ T cells persists. In this study,patients received HAART with or without recombinant IL-2, inthe hope that IL-2 therapy would enhance the clearance ofthese latently infected cells — by a combination of activationand upregulation of HIV expression and improved immune func-tion. Replication-competent virus could still be isolated aftertherapy in all the patients who received HAART alone, but notin 6 out of 14 patients who had additional IL-2 therapy. In threeof these patients, virus could not be recovered from culture ofvery large numbers of CD4+ T cells or even from cells frominguinal lymph nodes biopsied in two donors. Although this wasa cross-sectional study and was not randomised, there is someroom for optimism that IL-2 therapy can augment HIV clearancein conjunction with HAART.

The antiviral activity of HIV-specific CD8+ CTL clones is lim-ited by elimination due to encounter with HIV-infectedtargets. McKinney DM, Lewinsohn DA, Riddell SR, GreenbergPD, Mosier DE: J Immunol 1999, 163:861-867.

Paper alert 479

imb5pap.qxd 10/14/1999 8:58 AM Page 479

•• Significance: This study highlights a potential limitation of theability of HIV-specific cytotoxic T lyphocytes (CTLs) to controlHIV infection in vivo, because they are rapidly eliminated oncontact with HIV-infected targets.Findings: Studies of the feasibility and efficacy of adoptiveimmunotherapy with HIV-specific CTLs in HIV-infected peoplehave shown that the infused CTLs have a shortened life-spanof a few days. Using a SCID-Hu mouse model, the authors ofthis report show that, although HIV-specific clones infused intoan infected mouse led to a transient fall in viral load of around1 log, the cells were eliminated within 7 days. No suchdestruction was seen using either the same clones in an unin-fected mouse or irrelevant clones in infected mice. Themechanism of CTL death in HIV-infected animals will requirefurther elucidation.

Genetic effects on immunity Selected by Jean-Laurent CasanovaInstitut National de la Sante et de la Recherche Medicale, HopitalNecker-Enfants Malades, Paris, France

Neutrophil-specific granule deficiency results from a novelmutation with loss of function of the transcription factorCCAT/enhancer binding protein εε. Lekstrom-Himes J, DormanSE, Kopar P, Holland SM, Gallin JI: J Exp Med 1999,189:1847-1852.•• Significance: CCAT/enhancer binding protein ε (C/EBPε)deficiency was found in a patient with neutrophil-specific gran-ule deficiency (SGD), providing the first genetic etiology for thisrare human immunodeficiency.Findings: A patient with severe and recurrent bacterial infec-tions associated with SGD was investigated. Defectiveneutrophil chemotaxis and bactericidal activity and lack of neu-trophil secondary granules are distinctive features of thiscondition. The phenotypic resemblance with C/EBPε-knockoutmice led to the identification of a homozygous frameshift smalldeletion in the second exon of the patient’s C/EBPε gene. Themutant allele encodes a truncated 32 kDa major C/EBPε iso-form with loss of transcriptional activity. SGD thus definesseveral roles of human C/EBPε in myeloid differentiation.

Cancer Selected by Paul R WalkerUniversity Hospital Geneva, Geneva, Switzerland

The telomerase catalytic subunit is a widely expressedtumor-associated antigen recognized by cytotoxic T lym-phocytes. Vonderheide RH, Hahn WC, Schultze JL: Immunity1999, 10:673-679. •••• Significance: The identification of new class-I-restricted,tumour-associated antigens expressed by human tumours isalways of interest to cancer immunologists but their exploitationin immunotherapies is not always feasible. This study identifiesa protein that may come close to the dream of a ‘universal’tumour antigen — expressed by 85% of human tumours andwith a defined HLA-A2-binding epitope. Findings: High telomerase activity is a hallmark of the majorityof human cancers but it is at low levels in most normal cells.Vonderheide et al. reasoned that the telomerase catalytic sub-unit (hTERT) may be a useful source of tumour-associatedantigens and screened the sequence for potential HLA-A*0201-binding peptides. One of the selected peptides wassuccessfully used to generate cytotoxic T lymphocyte (CTL)lines from normal donors that lysed hTERT+ tumour cells in anMHC-restricted manner. Tumour lines of different histological

origin were killed, as well as certain tumour cells ex vivo. Onenormal cell target showed sensitivity to hTERT-specific CTLs —CD40-activated B cells. Probably only in vivo studies will revealwhether this potential autoreactivity proves to be an impedi-ment for the future application of this otherwise promisingtumour antigen.

Presentation of out-of-frame peptide/MHC class I com-plexes by a novel translation initiation mechanism.Malarkannan S, Horng T, Shih PP, Schwab S, Shastri N:Immunity 1999, 10:681-690.•• Significance: It has never been fully explained why ‘cryptic’peptides arising from apparently out-of-frame sequences areoccasionally recognised by tumour- or allo-specific T cells. Thisstudy describes the functioning of a novel translation initiationmechanism that clarifies this issue and suggests that the poten-tial array of epitopes available for T cell immunosurveillance maybe wider than previously thought. Findings: Malarkannan et al. identified alternative translationinitiation codons to the conventional AUG codon that weredecoded as leucine rather than the canonical methionine.The results of this work are consistent with a small fractionof ribosomes generating novel translation products, gener-ally short peptides of little physiological significance to thecell but of potential immunological significance. Indeed,these peptides perhaps increase the chances of tumourderived mutations being detected by class-I-restrictedCD8+ T cells.

Inhibition of cell growth and induction of apoptotic celldeath by the human tumor-associated antigen RCAS1.Nakashima M, Sonoda K, Watanabe T: Nat Med 1999,5:938-942.•• Significance: Spontaneous or induced antitumour responsesare frequently ineffectual, even for antigenic tumours, possiblyimplicating cancer immune escape mechanisms. In this report,Nakashima et al. describe how RCAS1 may play a role; thismolecule is expressed by several human tumours and showsimmunosuppressive properties in vitro. The in vivo implicationsremain to be directly determined but efficacious immunotherapymay need to take the effects of RCAS1 into account.Findings: The RCAS1 molecule is a membrane protein origi-nally identified using a monoclonal antibody against a humanuterine adenocarcinoma cell line. This paper now characteris-es RCAS1 and demonstrates that it is expressed by uterineand ovarian tumours as well as by nongynaecological cancers.The receptor for RCAS1 was found on normal hematopoieticcells and lymphocytes as well as on certain tumour cell lines —but only those that were negative for RCAS1. Recombinant orsoluble RCAS1 inhibited proliferation of preactivated T cellsand could also induce apoptosis of CD3- and/or IL-2-activated lymphocytes.

CD40 activation in vivo overcomes peptide-induced periph-eral cytotoxic T-lymphocyte tolerance and augmentsanti-tumor vaccine efficacy. Diehl L, den Boer AT,Schoenberger SP, van der Voort EI, Schumacher TN, Melief CJ,Offringa R, Toes RE: Nat Med 1999, 5:774-779.

ANDConversion of tumor-specific CD4+ T-cell tolerance to T-cellpriming through in vivo ligation of CD40. Sotomayor EM,Borrello I, Tubb E, Rattis FM, Bien H, Lu Z, Fein S,Schoenberger S, Levitsky HI: Nat Med 1999, 5:780-787.

480 Paper alert

imb5pap.qxd 10/14/1999 8:58 AM Page 480

•• Significance: As major strides are made in identifying tumour-expressed antigens recognised by CD4+ and CD8+ T cells,one outstanding fear is that defined subunit vaccines mayinduce specific tolerance rather than an efficient antitumourresponse. These two papers suggest that CD40 activation invivo may provide the switch for reversing tolerance of eitherCD4+ cells or CD8+ cells or it may otherwise augment a sub-optimal antitumour response.Findings: The approach taken by both of these studies isbased on the principle that CD40 ligation on antigen-pre-senting cells in vivo should enhance immune responses. Diehlet al. use a model in which two tolerising peptides, normallygiving rise to systemic specific CTL tolerance, could insteadinduce CTL priming if administered with an activating anti-body against CD40. Furthermore, in another system, apeptide vaccine with little effect on survival of tumour-bearingmice was rendered efficacious after coadministration withanti-CD40. This led to long-term survival of 70% of the mice.Concerning the studies of Sotomayor et al., function of CD4+

T cells bearing a transgenic TCR specific for influenzahaemagglutinin (HA) was analysed after their adoptive trans-fer in mice bearing an HA+ tumour. This procedure normallyrenders the transferred CD4+ cells tolerant but in vivo ligationof CD40 reversed this effect and could also inhibit toleranceinduced after intravenous administration of HA peptide.Moreover, some tumour regression was noted in mice treatedwith an HA vaccine and adoptive T cell transfer if the micewere also treated with anti-CD40.

TransplantationSelected by Kathryn Wood and Andrew BushellJohn Radcliffe Hospital, Oxford, UK

Cardiac allograft tolerance induced by intra-arterial infusionof recombinant adenoviral CTLA4-Ig. Yang Z, Rostami S,Koberlein B, Barker CF, Naji A: Transplantation 199967:1517-1523.• Significance: The importance of the CD28–B7 pathway inT cell costimulation has led many groups to examine B7 block-ade as a possible route to T cell inactivation or tolerance intransplantation. The most widely used reagent in these studieshas been a CTLA-4–Ig fusion protein comprising the extracel-lular portion of CTLA-4 ligated to the Fc portion ofimmunoglobulin. In a variety of models, systemic administrationof CTLA-4–Ig alone can led to prolonged allograft or xenograftsurvival. However, in many cases CTLA-4–Ig monotherapydoes not lead to indefinite graft survival and neither does itappear to protect grafts from the vascular changes characteris-tic of chronic rejection. In this study Yang et al. have taken analternative approach to the administration of CTLA-4–Ig. Theyperfused rat hearts ex vivo with a recombinant adenovirusencoding CTLA-4–Ig in the hope of achieving prolonged localexpression of the fusion protein.Findings: In order to test the efficiency of expression in theirperfusion system, Yang et al. perfused hearts via the proximalaorta with adenovirus (Ad) expressing LacZ then looked forβ-gal expression 5 days post-transplant. They found abundantexpression in the endo-myocardium with reduced expressiondeeper in the heart. No information was given on expression inthe major blood vessels. In the two allogeneic strain combina-tions examined (Lewis to Wistar-Furth and Brown Norway toWistar-Furth), untreated hearts are rejected with a median sur-vival time of about 12 days. Ex vivo perfusion using normalsaline or the AdLacZ virus had no effect on the rate of rejection

but, in striking contrast, perfusion of the AdCTLA-4–Ig virus ledto median survival times of 235 –250 days without further ther-apy. RT-PCR showed that CTLA-4–Ig was expressed for atleast 77 days but could no longer be detected at 100 dayspost-transplant. Histology showed good preservation of themyocardium at 77 days post-transplant with little evidence ofchronic vascular changes. The results of perfusion withAdCTLA-4–Ig are particularly impressive when seen in the con-text of an additional group in which the hearts were perfusedwith soluble CTLA-4–Ig rather than the recombinant virus.These hearts were rejected with a median survival time of about19 days. However, it would have been interesting to comparethe graft survival in the AdCTLA-4–Ig group with that in a groupgiven systemic CTLA-4–Ig in an optimized protocol in order toassess more fully the potential of the AdCTLA-4–Ig approach.Although perfusion with the AdCTLA-4–Ig virus led to long-term graft survival, the animals were not tolerant. Donor-specificskin grafts were rejected at control rates and, more important-ly, this also resulted in rejection of the primary hearts. Despitethe failure to induce true tolerance, the graft survival data sug-gest that this type of approach might form the basis ofcombined immunosuppressive protocols and clearly warrantsfurther examination.

Long-term survival and function of intrahepatic islet allo-grafts in rhesus monkeys treated with humanizedanti-CD154. Kenyon NS, Chatzipetrou M, Masetti M, RanuncoliA, Oliveira M, Wagner JL, Kirk AD, Harlan DM, Burkly LC,Ricordi C: Proc Natl Acad Sci USA 1999, 96:8132-8137.• Significance: Insulin therapy is the treatment of choice formost patients with insulin-dependent diabetes mellitus (IDDM)and although very successful in the short term, it is unable toprevent many of the chronic complications of this disease.Allogeneic transplantation of isolated islets of Langerhans hasbeen shown to be successful in several animal models of dia-betes and has been carried out in a relatively small number ofdiabetic patients. However, the immunogenicity of islets and/ortheir extreme sensitivity to immune-mediated damage has limit-ed the success of islet transplantation in man. In ths paper,Kenyon et al. have examined the effect of blockade of CD40—CD40L in a clinically relevant primate islet transplant model.Findings: Following pancreatectomy-induced diabetes, rhesusmonkeys received an intrahepatic transplant of MHC-mis-matched islets under cover of anti-CD40L induction therapy(humanized anti-CD154, hu5C8, on days –1, 0, 3 and 10 or–1, 0, 3, 10 and 18, relative to transplantation on day 0) fol-lowed by a monthly maintenance dose. Islet engraftment,long-term function and insulin dependence were seen in all sixanimals (range >125 to >476 post-operative days). Althoughfour of the six animals required small doses of insulin 7–14 dayspost-transplant and one animal required three additional dosesof hu5C8 to resolve a rejection episode 2 months post-trans-plant, all became insulin independent in the long term. Mostsignificantly, hu5C8 therapy was discontinued in three animalsabout 12 months post-transplant. All three of these animalsremained normoglycemic without further therapy. When seen inthe light of a report from last year (SM Rose, N Blustein, NRotrosen: Recommendations of the expert panel on ethicalissues in clinical trials of transplant tolerance. Transplantation1998 66:1123-1125.), these data suggest that clinical trials ofCD40–CD40L blockade in islet and kidney transplantation canbe anticipated with cautious optimism. See also AD Kirk et al.(Treatment with humanized monoclonal antibody against

Paper alert 481

imb5pap.qxd 10/14/1999 8:58 AM Page 481

CD154 prevents acute renal allograft rejection in nonhumanprimates. Nat Med 1999, 5:686-693.) and NS Kenyon et al.(Long-term survival and function of intrahepatic islet allografts inbaboons treated with humanised anti-CD154. Diabetes 1999,48:1473-1481.).

Atopic allergy and other hypersensitivities Selected by Santa Ono and Michael RadosevichHarvard Medical School, Boston, Massachusetts, USA

The transcription factor c-Maf controls the production ofinterleukin-4 but not other Th2 cytokines. Kim J, Ho IC,Grusby M, Glimcher L: Immunity 1999, 10:745-761.•• Significance: CD4+ T helper cells can differentiate into twodistinct subsets — Th1 cells produce the cytokines IFN-γ andlymphotoxin whereas Th2 cells produce IL-4, IL-5, IL-6, IL-10and IL-13. IL-4 plays a central role in the development and reg-ulation of allergic immune responses and is critical for thedifferentiation of Th cell precursors into mature Th2 cells. Micethat do not have IL-4 or the downstream IL-4 signaling moleculeStat6 do not develop substantial numbers of Th2 cells.Previous work has suggested that the transcription factor c-Mafcontrols the expression of IL-4 but it was not known if c-Mafwas responsible for the expression of other Th2 cytokine genes.Findings: The investigators used mice in which the c-Maf genehas been disrupted to examine the role of this transcription fac-tor in the production of cytokines expressed by Th2 cells. It wasdemonstrated that IL-4 production was severely impaired inboth Th2 cells and in NK1.1 T cells. However, spleen cells fromc-Maf-deficient mice — when differentiated in the presence ofexogenous IL-4 — produce normal levels of IgE, IL-13 and otherTh2 cytokines. Therefore c-Maf has a critical and selective func-tion in the regulation of the IL-4 gene in vivo.

A novel human CC chemokine, eotaxin-3, which isexpressed in IL-4-stimulated vascular endothelial cells,exhibits potent activity toward eosinophils. Shinkai A,Yoshisue H, Koike M, Shoji E, Nakagawa S, Saito A, Takeda T,Imabeppu S, Kato Y, Hanai N et al.: J Immunol 1999,163:1602-1610.•• Significance: It is now clear that members of theβ-chemokine family play critical roles in recruiting leukocytes tosites of inflammation. In addition, it is clear that the cytokine IL-4plays a major role in local allergic inflammation by promoting theextravasation of eosinophils via the vascular endothelium.These investigators isolate a new CC chemokine, eotaxin-3,which is IL-4-dependent and which is a potent chemoattractantof eosinophils. Findings: Using RNA isolated from IL-4-stimulated HUVECcells, the investigators isolated a novel CC chemokine desig-nated eotaxin-3. Recombinant protein generated from thecDNA acts as an eosinophil chemoattractant both in vitro andin vivo. The protein binds to CCR-3 and is induced by IL-4.Unlike eotaxin and RANTES, TNF-α and IFN-γ are unable toinduce eotaxin-3 expression.

Activation of mitogen-activated protein kinase regulateseotaxin-induced eosinophil migration. Boehme SA, SullivanSK, Crowe PD, Santos M, Conlon PJ, Sriramarao P, Bacon KB:J Immunol 1999, 163:1611-1618.• Significance: Numerous CC chemokines attract eosinophilsboth in vitro and in vivo. Eotaxin displays a highly specificchemoattractive potential for eosinophils in vivo. While it isknown that eotaxin binds primarily to CCR3, the mechanism by

which this binding regulates eosinophil migration is poorlyunderstood. This paper sheds light on this process.Findings: Treatment of eosinphils with eotaxin induces thephosphorylation of mitogen-activated protein kinases (MAPKs)p42 and p44. The MAPK inhibitor PD98059 decreases eotaxin-induced eosinphil rolling in vivo and chemotaxis in vivo. Actinpolymerization and rearrangement is inhibited in eosinophilstreated with this inhibitor. These data suggest that signalingthrough p42/p44 MAPK induces cytoskeletal rearrangementsrequired for eosinophil chemotaxis.

The late, but not early, asthmatic response is dependent onIL-5 and correlates with eosinophil infiltration. Cieslewicz G,Tomkinson A, Adler A, Duez C, Schwarze J, Takeda K, LarsonKA, Lee JJ, Irvin CG, Gelfand EW: J Clin Invest 1999,104:301-308.• Significance: Allergic reactions in most tissue consist of bothan acute (early) phase and a late (chronic) phase. The late-phase reaction is characterized by an infiltration of eosinophilsinto that tissue. This paper describes the requirement for par-ticular Th2 cytokines in the late-phase reaction. Findings: Using a murine model of early and late phase reac-tions in the lung, the investigators show clearly that thelate-phase reaction is dependent on IL-5. The early-phase reac-tion, in contrast, does not require IL-5.

Autoimmunity Selected by Marc BonnevilleINSERM U 463, Institut de Biologie, Nantes, France

Serum amyloid P component controls chromatin degrada-tion and prevents antinuclear autoimmunity. BickerstaffMCM, Botto M, Hutchinson WL, Herbert J, Tenant GA, BybeeA, Mitchell DA, Cook HT, Butler PJG, Walport MJ, Pepys MB:Nat Med 1999, 5:694-697. • Significance: This study demonstrates for the first time animportant physiological role of serum amyloid P component(SAP), which may be to inhibit the formation of pathogenicautoantibodies against chromatin and DNA — probably by bind-ing to chromatin and regulating its degradation.Findings: SAP avidly binds to DNA and chromatin and permitssolubilization of native, long chromatin. SAP also binds in vivoto apoptotic cells and nuclear debris and may therefore partic-ipate in handling of chromatin that is exposed by cell death. Thisstudy shows that mice with targeted deletion of the SAP genedevelop a syndrome resembling human systemic lupus erythe-matosus, which is associated with antinuclear autoimmunityand severe glomerulonephritis. The rate of chromatin degrada-tion is faster in SAP—/— mice than in wild-type mice, suggestingthat SAP stabilizes chromatin in vivo and that in the absence ofSAP the more aggressive degradation of insoluble chromatinmay enhance its immunogenicity.

Inherited human Caspase 10 mutations underlie defectivelymphocyte and dendritic cell apoptosis in autoimmunelymphoproliferative syndrome type II. Wang J, Zheng L,Lobito A, Chan FKM, Dale J, Sneller M, Yao X, Puck JM, StrausSE, Lenardo MJ: Cell 1999, 98:47-58. •• Significance: This genetic analysis of patients with autoim-mune lymphoproliferative syndromes (ALPS) provides the firstevidence for a key role for caspases in autoimmunity and in lym-phocyte and dendritic cell (DC) homeostasis.Findings: Caspases are cysteine proteases that play a crucialin role apoptosis. This study describes two families with ALPS

482 Paper alert

imb5pap.qxd 10/14/1999 8:58 AM Page 482

type II, characterized by autoimmunity and defects in T lympho-cyte and DC homeostasis, that carry mis-sense mutations in thegene for Caspase 10. These mutations result in decreasedenzymatic activity and diminished apoptosis induced by the

Fas-ligand and TRAIL death receptors. Furthermore, this studyprovides strong evidence for a novel TRAIL-dependent apop-totic process that controls DC turnover and possibly takes partin the maintenance of tolerance.

Paper alert 483

imb5pap.qxd 10/14/1999 8:58 AM Page 483