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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, 11:1–8

http://biomednet.com/elecref/0952791501100001

© Elsevier Science Ltd ISSN 0952-7915

Contents (chosen by)1 Antigen recognition (Elliott)2 Innate immunity (Bonneville)3 Lymphocyte development (Kruisbeek)4 Immunological techniques (Liu)4 Lymphocyte activation and effector functions (Ono)5 Immunity to infection (Bonneville)5 HIV (Rowland-Jones)5 Genetc effects on immunity (Casanova)5 Cancer (Walker)6 Transplantation (Wood and Bushell)7 Atopic allergy and hypersensitivity (Ono)7 Autoimmunity (Bonneville)

• of special interest•• of outstanding interest

Antigen recognitionSelected by Tim ElliottJohn Radcliffe Hospital, Oxford

A protective cytotoxic T cell response to a subdominantepitope is influenced by the stability of the MHC classI/peptide complex and the overall spectrum of viral pep-tides generated within infected cells. Gallimore A,Hombach J, Dumrese T, Rammensee H-G, Zinkernagel R,Hengartner H: Eur J Immunol 1998, 28:3301-3311.

ANDImmunodominance in the CTL response against minor his-tocompatibility antigens: interference between respondingT cells rather than presentation of epitopes. Wolpert E,Grufman P, Sandberg J, Tegnesjo A, Karre K: J Immunol 1998,161:4499-4505.• Significance: Understanding the mechanisms underpinningthe immunodominant recognition by T cells of some peptide epi-topes over others is crucial for the rational design of vaccines aswell as for a better appreciation of such processes as graft rejec-tion and autoimmunity. It is becoming clear that there are manydifferent ways by which immunodominance (and subdominanceor subordinance) is achieved. These two studies highlight twovery different mechanisms. The first study illustrates the role ofantigen processing and presentation; here, subdominance corre-lated with poor stability of the complex of MHC with peptide, butthe authors also suggest that competition for binding to class IMHC molecules in the endoplasmic reticulum could also be adetermining factor. The second study indicates how events fol-lowing antigen recognition can also play a role.Findings: Gallimore et al. identified a third H-2Db-restrictedcytotoxic T lymphocyte (CTL) epitope, gp117–125, from withinthe envelope glycoprotein of lymphocytic choriomeningitis virus

(LCMV) gp160 which is only presented in cells infected with arecombinant vaccinia virus encoding gp160 that lacks the twoimmunodominant epitopes. The epitope is therefore subdomi-nant. The ensuing response to this epitope in mice is protectivetowards subsequent challenge with LCMV8.7B23 (which lacksthe two dominant epitopes) but not towards wild-type LCMV.The complex of H-2Db with gp117–125 was unstable at the cellsurface with a half-time of less than 2 hours at 37oC andgp117–125 could only be eluted from the surface of cellsinfected with LCMV8.7B23 but not from those infected withwild-type LCMV. These results suggest that binding of the low-affinity subdominant epitope to H-2Db can be competitivelyinhibited by the dominant epitopes as complexes of class I MHCwith peptide are assembled in the endoplasmic reticulum.Wolpert et al. showed that of the 40 or so minor histocompati-bility antigens that differ between C57BL/64 and BALB.Bmice, the allospecific CTL response focused on two dominantand three subdominant peptide epitopes. As in the study byGallimore et al., responses to the subdominant epitopes areonly observed in cases where the dominant epitopes are notgenerated; however, in this case, the authors have shown thatthe subdominant epitopes are generated and presented effi-ciently even in the presence of the dominant epitopes. Theresponse hierarchy was only seen when both dominant andsubdominant epitopes were expressed on the same antigen-presenting cells (APCs). Immunisation of mice with APCsexpressing both dominant and subdominant epitopes elicited aresponse to the dominant epitope only, whereas immunisationwith a mixture of APCs expressing either dominant or subdomi-nant epitopes elicited a dual response. When CTLs primedindependently to dominant and subdominant epitopes were re-stimulated with APCs bearing both, the hierarchy wasre-established. These results suggest then that a mechanisminvolving interference between CTLs with different specificitiesrecognising antigen presented by the same APC can accountfor the phenomenon of immunodominance.

MHC class I molecules compete in the endoplasmic reticu-lum for access to transporter associated with antigenprocessing. Knittler M, Gulow K, Seelig A, Howard J:J Immunol 1998, 161:5967-5977.• Significance: Class I MHC molecules are loaded with anti-genic peptides in the endoplasmic reticulum (ER). Duringloading they associate with many ER-resident cofactors includ-ing TAP, tapasin, calreticulin, ERp57 and calnexin. Very little isknown about the functional significance of these interactionsand, in particular, the in vivo relevance of TAP-binding is contro-versial. This study shows that class I MHC molecules competefor TAP binding in the ER with no detrimental effect on antigenpresentation and it supports the view that the TAP interaction isnot a prerequisite for loading class I MHC. The study alsoimplies that the apparent coevolution of alleles of class I MHCand TAP2 with compatible peptide-binding specificities may nothave necessarily required the two to be physically associated.Findings: The rat class I MHC allele RT1Aa binds peptides trans-ported into the ER by the TAP2-A allele but not the TAP2-B allele,whereas RT1Au binds peptides transported by both. In cellsexpressing only TAP2-B, RT1Aa is nonfunctional as an antigen-presenting molecule and is retained in the ER. In doing so it

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accumulates in a complex containing TAP and other ER-residentcofactors. This accumulation blocks the association between TAPand RT1Au; nevertheless, RT1Au matures normally and reachesthe cell surface with normal kinetics. Normal maturation of RT1Aa

requires the co-expression of TAP2-A. In cells expressing bothclass I MHC alleles and both TAP2 alleles, RT1Aa and RT1Au

associate indiscriminately with the two TAP alleles.

Prevention of acute allograft rejection by antibody target-ting of TIRC7, a novel T cell membrane protein. Utku N,Heinemann T, Tullius SG, Bullwin GC, Beinke S, Blumberg RS,Beato F, Randall J, Kojima R, Busconi L et al.: Immunity 1998,9:509-518.•• Significance: This paper reports a previously unidentified Tcell surface glycoprotein that plays an essential role in T cellactivation in the type 1 immune response. A subset of antibod-ies raised against it inhibit T cell proliferation in vitro andprolong kidney allograft survival when administered in vivo.This molecule may therefore be an effective target for passivetherapeutic immunointervention.Findings: Using differential-display RT-PCR from restingversus alloantigen-stimulated T cells, the authors isolated anovel mRNA that was used to probe a human T cell library;from this, the gene — called TIRC7 (T cell immune responsecDNA 7) — was isolated and sequenced. The 1.8 kilobaseopen reading frame (GenBank accession number AF025374),expressed exclusively in immunological tissues, showed somehomology (12–71%) to the vacuolar proton pump H+-ATPaseand is an alternatively spliced form of the human OC116 genethat is expressed in osteoclastoma cells. There is a 20-foldincrease in TIRC7 mRNA expression in allostimulated T cells,peaking at 24 hours and returning to baseline by 72 hours.Antisera raised to TIRC7 peptides localised expression to thecell surface and possibly endosomes. Both a subset of theseantisera and soluble TIRC7 inhibited allostimulation whenadded to a mixed-lymphocyte culture. This inhibition was spe-cific for the type 1 response (T cells secreting IL-2 and IFN-γ)and was partially overcome by the addition of recombinantIL-2. When administered to rats (24 hours before and 0, 1, 2, 4and 6 days after bilateral renal allografts) survival of the allo-grafts was significantly prolonged and the transplanted organsshowed little of the diffuse mononuclear cell infiltration andtissue necrosis seen in the allografts of control-treated rats.

Innate immunitySelected by Marc BonnevilleINSERM U 211, Institut de Biologie, Nantes

Lipid A acylation and bacterial resistance against vertebrateantimicrobial peptides. Guo L, Lim KB, Poduje CM, Daniel M,Gunn JS, Hackett M, Miller SI: Cell 1998, 95:189-198.•• Significance: This study provides a molecular basis for ageneral bacterial resistance mechanism against antimicrobialpeptides produced by innate immune cells. Findings: Cationic antimicrobial peptides (CAMPs) areamphipatic molecules produced by a variety of immune cellsfrom invertebrate and vertebrate animals. Gram-negative patho-genic bacteria, such as Salmonella species, have developedspecific CAMP-resistance mechanisms that involve transcrip-tional activation of specific genes by the PhoP–PhoQ signaltransduction system. This study identifies a PhoP-activated genethat promotes resistance to CAMPs and is required for the regu-lated acylation of lipid A, a major component of the bacterialouter membrane. Increased acylation of lipid A is associated with

alterations of membrane permeability and is also observed inother Gram-negative bacteria placed under conditions leading toincreased CAMP resistance. A general model for the mechanismof inducible CAMP-resistance through outer membrane modifi-cation is proposed, which could have important implications forthe development of new antimicrobial agents.

Regulation of the proinflammatory effects of Fas ligand(CD95L). Chen JJ, Sun Y, Nabel GJ: Science 1998,282:1714-1716.•• Significance: The authors describe a novel tolerance mech-anism involving suppression of neutrophil activation bytransforming growth factor (TGF)-β.Findings: Fas ligand (CD95L) inhibits T cell function inimmune-privileged organs such as the eye but induces inflam-matory responses in immunocompetent tissues. Accordinglytransfection of CD95L into a tumor cell line results in tolerancewhen cells are injected in the eye but in accelerated rejectionwhen they are injected subcutaneously. It is shown here thatrejection of CD95L+ tumors that are injected subcutaneouslyis caused by neutrophils activated by CD95L. Survival ofCD95L-transfectants in the ocular space is due to the pres-ence of TGF-β, which blocks CD95L-induced neutrophilactivation. In vitro, CD95L-transfectants trigger neutrophilcytotoxicity and p38 (mitogen-activated protein kinase) activity;both of these functions are inhibited by TGF-β.

Identification of two distinct mechanisms of phagocytosiscontrolled by different Rho GTPases. Caron E, Hall A:Science 1998, 282:1717-1720.•• Significance: Complement receptors and immunoglobulinreceptors are involved in phagocytosis of opsonized micro-organisms by macrophages, but only uptake by the latterreceptors results in an inflammatory response. This study pro-vides a molecular explanation for these distinct biologicaloutcomes that are associated with phagocytosis; it could haveimportant implications for our general understanding of the reg-ulation of inflammatory responses during apoptosis andinfectious processes. Findings: This study identifies two distinct mechanisms ofphagocytosis. Type I is used by the immunoglobulin receptorand is dependent on the activation of two small guanosinetriphosphatases (GTPases), Cdc42 and Rac. Type II is used bycomplement receptors and is mediated by another smallGTPase, Rho. Because Cdc42/Rac, unlike Rho, are essentialcomponents of signalling pathways leading to release of reac-tive oxygen species and proinflammatory factors, these resultsexplain why phagocytosis that is mediated by type I (but nottype II) receptors is accompanied by an inflammatory response.

Mouse CD94/NKG2A is a natural killer cell receptor for thenonclassical major histocompatibility complex (MHC)class I molecule Qa-1b. Vance RE, Kraft JR, Altman JD,Jensen PE, Raulet DH: J Exp Med 1998, 188:1841-1848.• Significance: This is the first instance in which an NKR andits MHC class I ligand are shared by mice and humans. Thisstudy therefore provides the first direct evidence that MHC-dependent control of NK cell activation is a primitive functionthat appeared before speciation between primates androdents; it indicates that mouse models are appropriate tostudy the in vivo function of human NKRs. Findings: Self/nonself discrimination by NK cells is controlledby receptors (NKRs) that are able to deliver inhibitory signals

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upon interaction with MHC class I molecules. While NKRsbelonging to either C-type (calcium-dependent)-lectin orimmunoglobulin families have been identified in mice andhumans, they greatly differ in their structure and ligand speci-ficity. This study reports the cloning of a mouse heterodimericNKR that is highly homologous to the human CD94–NKG2ANKR and shows that, like its human counterpart, mouseCD94–NKG2A binds to a weakly polymorphic class-I-like mol-ecule that is complexed with a peptide derived from the signalsequence of some classical MHC class I molecules.

Lymphocyte developmentSelected by Ada M KruisbeekThe Netherlands Cancer Institute, Amsterdam

Schlafen, a new family of growth regulatory genes thataffect thymocyte development. Schwartz DA, Katayama CD,Hedrick SM: Immunity 1998, 9:657-668.• Significance: Positive selection of thymocytes remains oneof the most intriguing immunological phenomena: interactionsbetween TCRs on CD4+ CD8+ (double positive, DP) thymo-cytes and complexes of peptides with MHC molecules onthymic stroma result in rescue from apoptosis and further dif-ferentiation (positive selection), but the molecular events thatdirect this process are largely obscure. In this study, genes thatare differentially expressed and transcriptionally upregulated asa result of positive selection are isolated and characterized.Findings: Subtractive hybridization was performed on thymus-derived cDNA libraries from TCR-transgenic mice in whichdifferential MHC expression is permissive or nonpermissive forpositive selection. A novel gene family, termed Schlafen (Slfn),was identified and expression of its prototype member Slfn1was found to be upregulated 100-fold during the transition fromDP to CD4+ CD8– or CD8+ CD4– thymocytes. Ectopic expres-sion of Slfn1 early in the T cell lineage resulted in a profoundblock in positive selection. Together with the observation thatexpression of Slfn1 in fibroblasts and thymoma cells retards orablates cell growth, it appears that control of the cell cycle bySlfn gene products may contribute to thymocyte selection.

Receptor editing occurs frequently during normal B celldevelopment. Retter MW, Nemazee D: J Exp Med 1998,188:1231-1238.• Significance: In immunoglobulin-transgenic mice expressingan autoreactive B cell receptor (BCR), exposure to autoantigencan induce receptor editing. This term refers to a process duringwhich allelic exclusion is prevented or reversed through ongoinglight (L)-chain rearrangements, resulting in altered BCR speci-ficity. It has not been investigated — up to this point — to whatextent receptor editing occurs in normal, non-immunoglobulin-transgenic B cells and the present study addresses this issue.Findings: To estimate the extent of receptor editing in normalB cells, advantage was taken of the fact that λ L-chains usuallyrearrange after κ L-chains. By analysing VκJκ recombinationremnants inactivated by subsequent recombining sequence(RS) arrangements in IgM+ λ+ B cells, an estimate can beobtained of how frequently in-frame κ genes fail to suppress λgene rearrangements. It turns out that nearly half of all IgM+ λ+

B cells express RS-inactivated, but in-frame, VκJκ joints. Thesefindings are consistent with the notion that receptor editingoccurs at a high frequency in normal B cells.

The JNK pathway regulates the in vivo delection of imma-ture CD4+ CD8+ thymocytes. Rincón M, Whitmarsh A, Yang

DD, Weiss L, Dèrijard B, Jayaraj P, Davis RJ, Flavell RA: J ExpMed 1998, 188:1817-1830.• Significance: Do different signaling pathways control nega-tive and positive selection of thymocytes? Both involveTCR-mediated recognition of MHC–peptide complexes in thethymus, but whether they result from quantitative or qualitativedifferences in signalling remains unclear. This study indicatesthat the activation of the c-Jun NH2-terminal kinase (JNK)specifically controls negative, but not positive, selection.Findings: Following the observation that JNK is activated invivo in response to stimuli triggering negative selection, micewere produced that overexpress a dominant-negative mutantof JNK1 (dnJNK1) transgenically in thymocytes and peripheralT cells. Activation of JNK is compromized in dnJNK1 thymo-cytes, indicating that the endogenous JNK is inhibited bydnJNK1. Most importantly, dnJNK1-transgenic mice exhibitnormal positive selection while negative selection induced byTCR signals and signals from the thymic microenvironmentare significantly reduced. The JNK pathway thus contributesto negative selection. Together with a previous report showingspecific involvement of the mitogen-activated protein-kinasepathway in positive selection (J Alberola-Ila et al.: Positiveand negative selection invoke distinct signaling pathways.J Exp Med 1996, 184:9-18), these results support a qualita-tive model of thymocyte selection.

RAG reexpression and DNA recombination at T cell recep-tor loci in peripheral CD4+ T cells. McMahan CJ, Fink PM:Immunity 1998, 9:637-647.• Significance: Just as receptor editing in B cells represents ameans to change specificity of the B cell receptor (BCR), Tcells may also create novel antigen receptors. In the presentstudy, it is shown that allelic exclusion at the TCR β-chain locuscan be overcome as a result of V(D)J recombination in periph-eral CD4+ T cells.Findings: In transgenic mice expressing a Vβ5 transgene onthe C57BL/6 background, transgene expression wanes withage, resulting in accumulation of Vβ5– T cells. Peripheral Vβ5–

T cells re-express recombination-activating gene (RAG)1 andRAG2 genes, accumulate signal-end intermediates indicativeof ongoing V(D)J recombination at TCR loci and express cellsurface TCRs encoded by endogenous TCR genes. Thesefindings parallel those for receptor editing in B cells and repre-sent an alternative to deletion of autoreactive T cells formaintenance of tolerance.

The Ets-1 transcription factor is required for the develop-ment of natural killer cells in mice. Barton K, Muthusamy N,Fischer C, Ting C-N, Waluns TL, Lanier LL, Leiden JM:Immunity 1998, 9:555-563.• Significance: The molecular pathways that regulate natural killer(NK) cell development are poorly understood and it is particularlyunclear which pathways distinguish the development of NK cellsfrom development of the closely related B and T cells. The tran-scription factor Ets-1 is shown in the present study to be requiredfor development and/or survival of the NK cell lineage in mice.Findings: Ets-1-deficient mice produced by gene targetingexhibit normal development of T lymphocytes, B lymphocytes,erythrocytes, monocytes and neutrophils. In sharp contrast,Ets-1-deficient mice have significantly reduced numbers of NKcells and lack NK cell activity in vitro and in vivo. Ets-1 thusappears to define a transcriptional pathway that distinguishes Tand B cell development from NK cell development.

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Immunological techniquesSelected by Yang LiuNew York University, New York

Models of immune memory: on the role of cross-reactivestimulation, competition, and homeostasis in maintainingimmune memory. Antia R, Pilyugin SS, Ahmed R: Proc NatlAcad Sci USA 1998, 95:14926-14931.• Significance: This appears to be the first approach that com-bines the dynamics of antigen-specific stimulation andinteractions between different lineages to build mathematicalmodels that address the role of cross-reactive antigen, compe-tition and homeostasis in maintaining immune memory.Findings: Firstly, if homeostatic control regulates the total pop-ulation of memory cells, then — for a wide range ofparameters — immune memory will be long-lived (with a half-lifeof over a year) in the absence of persistent antigen; secondly,longevity of memory in this situation will be insensitive to therelative rates of cross-reactive stimulation, the rate of turnoverof immune cells and the precise mechanisms involved in main-tenance of homeostasis.

Correlative microscopy using FluoroNanogold on ultrathincryosections: proof of principle. Takizawa T, Suzuki K,Robinson JM: J Histochem Cytochem 1998, 46:1097-1102.• Significance: This provides a clear demonstration thatFluoroNanogold can be used as second-step reagent in ultra-thin sections for examination using both fluorescent-lightmicroscopy and electron microscopy.Findings: Using the FluoroNanogold reagent and lactoferrin — amarker for human neutrophils — as the target protein, theauthors found that spatial resolution of the fluorescence signalin light microscopy is compatible with that of the signal in elec-tron microscopy that is derived from the gold. Thus, theFluoroNanogold can be used as a probe for high-resolution cor-relation between immunofluorescence and electron microscopy.

Lymphocyte activation and effector functionsSelected by Santa OnoSchepens Eye Research Institute, Cambridge, Massachusetts

Selective up-regulation of chemokine receptors CCR4 andCCR8 upon activation of polarized human type 2 Th cells.D’Ambrosio D, Iellem A, Bonecchi R, Mazzeo D, Sozzani S,Mantovani A, Sinigaglia F: J Immunol 1998, 161:5111-5115.• Significance: A complex process of adhesion-molecule inter-actions and chemokine-receptor interactions mediates theextravasation of immune cells to peripheral tissues. Followingup recent reports of chemokine-receptor expression on Thelper (Th) cells, this manuscript describes the effect of lym-phocyte activation on chemokine-receptor expression. Thesedata are significant, as they help define likely roles for thesereceptors in the positioning of effector T cells. Findings: In contrast with other receptors, the chemokine recep-tors CCR4 and CCR8 are induced on Th2 cells following TCRengagement. Functional analysis of these activated T cells indi-cates that they are in fact responsive to appropriate chemokineligands. A similar phenomenon is also observed in CD8+ T cells.

Structure of an IκκBαα/NF-κκB complex. Jacobs MD, Harrison C:Cell 1998, 95:749-758.•• Significance: The inhibitory protein IκBα forms a complex withthe transcription factor NF-κB in the cytoplasm of ‘resting’ cells.When NF-κB is activated in immune and inflammatory responses,IκBα is degraded by proteosomes. This degradation unmasks the

nuclear localization signal of NF-κB and allows its translocation tothe nucleus and the activation of target genes. This paperdescribes the X-ray structure of the IκBα ankyrin-repeat domainbound to a truncated NF-κB. This structure explains the mode ofinteraction between the proteins and may allow the design of newanti-inflammatory drugs.Findings: Six IκBα ankyrin-repeats face the carboxy-terminaldomains of the Rel homology regions. This continuous contactsuggests a combinatorial mechanism of complex formation.Two ankyrin-repeats cover the α-helical region of the nuclearlocalization signal. The six ankyrin-repeats also appear toocclude the NF-κB DNA-binding cleft.

Inhibition of Th1 development mediated by GATA-3through an IL-4-independent mechanism. Ouyang W,Ranganath SH, Weindel K, Bhattacharya D, Murphy TL, ShaWC, Murphy KM: Immunity 1998, 9:745-755.• Significance: Flavell and co-workers initially described animportant role for the GATA-3 transcription factor in T helper(Th) cell development. They described a preferential expressionof GATA-3 in Th2 cells and presented evidence that it couldtransactivate Th2 cytokine promoters. This paper providesgreater mechanistic detail on the loss of GATA-3 expression inTh1 lymphocytes.Findings: The loss of GATA-3 requires IL-12 signaling throughsignal transducer and activator of transcription (STAT)4. GATA-3inhibits Th1 cytokine production independently of IL-4. Thisappears to function by blocking signal transduction through IL-12.

LAT is required for TCR-mediated activation of PLCγγ1 andthe Ras pathway. Finco TS, Kadlecek T, Zhang W, SamelsonLE, Weiss A: Immunity 1998, 9:617-626.• Significance: Weiss and co-workers have previously describedmutant subclones of the cell line Jurkat, which are defective insignal transduction through the TCR. In this manuscript, the inves-tigators show that the molecular basis of the defect in the sublineJ.CaM2 affects the recently cloned adapter protein pp36/LAT. Findings: Initial characterization of the cell line indicates thatcross-linking of the TCR fails to increase intracellular calciumlevels. MF-AT induction is defective, as is activation of the IL-2promoter. Examination of whole-cell lysates from wild-type andmutant clones indicates that the J.CaM2 subline exhibitsaltered patterns of protein-tyrosine phosphorylation.Specifically, expression of the newly isolated adapter proteinLAT is dramatically reduced in the mutant cell line.Reconstitution of LAT expression restores tyrosine phosphory-lation, calcium mobilization and IL-2 promoter activity. Takentogether, these data provide direct evidence for the importanceof the LAT protein in TCR signal transduction.

Inhibitory function of two NFAT family members in lymphoidhomeostasis and Th2 development. Ranger AM, Oukka M,Rengarajan J, Glimcher LH: Immunity 1998, 9:627-635.• Significance: Members of the nuclear factor of activated Tcells (NFAT) family of transcription factors respond to TCR-mediated signals and regulate expression of T-cell cytokines.This laboratory, as well as others, has been studying the bio-logical role of four NFAT proteins (NFATp, NFATc, NFAT3 andNFAT4) in lymphocyte effector function. This paper describesthe phenotype of mice lacking both NFATp and NFAT4. Findings: The NFATp/NFAT4-deficient mice exhibit profoundlymphoproliferative disease. This results from facile signal trans-duction via the TCR and from increased resistance to apoptosis

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resulting from defective FasL expression. The mice exhibit aller-gic blepharitis resulting from dramatically elevated IgE levels,which in turn stems from increased Th2-type cytokine produc-tion. The molecular basis for this phenotype probably resultsfrom unopposed occupancy of the IL-4 promoter by NFATc.

Immunity to infectionSelected by Marc BonnevilleINSERM U 211, Institut de Biologie, Nantes

Development of a natural model of cutaneous leishmaniasis:powerful effects of vector saliva and saliva preexposure onthe long-term outcome of Leishmania major infection in themouse ear dermis. Belkaid Y, Kamhawi S, Modi G, Valenzuela J,Noben-Trauth N, Rowton E, Ribeiro J, Sacks DL: J Exp Med1998, 188:1941-1953.• Significance: This study describes a novel model ofcutaneaous leishmaniasis that closely mimicks the natural con-ditions of infection in humans. It provides strong evidence thatimmunity to sand-fly saliva, a key component of natural trans-mission, deeply influences the outcome of exposure totransmitted parasites and therefore has important epidemiolog-ical and therapeutic implications.Findings: The authors have established a model of cutaneousleishmaniasis in which mice are inoculated subcutaneouslywith low doses of L. major promastigotes, with or without sali-vary gland sonicates (SGS) obtained from a natural vector.Co-inoculation of parasites and SGS resulted in exacerbationof dermal lesions and was associated with increased fre-quency of infiltrating epidermal cells producing type-2cytokines. All these effects were reversed by antisaliva antibod-ies in mice pre-exposed to SGS.

Regulation of host immune responses by modification ofSalmonella virulence genes. VanCott JL, Chatfield SN,Roberts M, Hone DM, Hohmann EL, Pascual DW, YamamotoM, Kiyono H, McGhee JR: Nat Med 1998, 4:1247-1252.• Significance: This paper provides the first evidence that twomajor virulence genes in Gram-negative bacteria elicit differenthost immune responses. The strategy proposed here could beuseful to devise new bacterial attenuation strategies formedical purposes.Findings: Attenuated Salmonella Pho– and Aro– mutantstrains, with disrupted phoP-phoQ and aro virulence genesrespectively, have strong potential as vaccines and antigen-carrier vehicles. Oral administration of a PhoP– strain promotedstrong innate immune responses of macrophages that weresufficient for bacterial clearance. In contrast, the Aro– mutantselicited stronger B and T cell responses which were requiredto clear the bacteria through an IFN-γ-dependent mechanism.

HIVSelected by Sarah Rowland-Jones Institute of Molecular Medicine, John Radcliffe Hospital, Oxford

Vaccine-induced cytotoxic T lymphocytes protect againstretroviral challenge. Hislop AD, Good MF, Mateo L,Gardner J, Gatei MH, Daniel RC, Meyers BV, Lavin MF,Suhrbier A: Nat Med 1998, 4:1193-1196.•• Significance: This paper demonstrates protection in sheepagainst infection with bovine leukaemia virus, using a peptidevaccine which elicits cytotoxic T lymphocytes (CTLs) recognis-ing a single dominant epitope.Findings: The aim of this work was to examine whether virus-specific CTLs elicited by immunisation are sufficient to protect

against retroviral infection, using the sheep model of infectionwith bovine leukaemia virus. A single, dominant, conservedCTL epitope was identified in the gp51 protein and theminimal epitope was defined. This was then administered as apeptide vaccine in incomplete Freund’s adjuvant to a cohort ofsheep with the appropriate class-I-MHC restricting moleculeand potent CTLs were elicited; however, only the four (out ofeight) sheep whose CTLs recognised both peptide-pulsedand virus-infected targets were completely protected fromvirus challenge. This may serve as a useful model system forvaccination against retrovirus infections in man.

Genetic acceleration of AIDS progression by a promotervariant of CCR5. Martin MP, Dean M, Smith MW, Winkler C,Gerrard B, Michael NL, Lee B, Doms RW, Margolick J,Buchbinder S et al.: Science 1998, 282:1907-1911.• Significance: This paper continues the exploration of the roleof host gene polymorphism in determining the rate of HIVdisease progression, focusing on haplotypes in the promoterregion of CCR5, which binds HIV (as well as chemokines).Findings: Several polymorphisms in the main CCR5 promoterwere identified and their linkage to the coding mutations inCCR2 and CCR5 were established. The distribution of thecomplete CCR2–promoter–CCR5 haplotypes was examined inmore than 2600 HIV-infected people enrolled in the principalHIV disease cohorts in the USA. Homozygotes for a particularcombination of polymorphisms in the promoter were signifi-cantly more likely to progress rapidly to AIDS, even though thishaplotype is linked to the protective CCR2-64I and CCR5 ∆32mutations. This confirms the importance of the CCR2–pro-moter–CCR5 region on chromosome 3 in determining clinicaloutcome and it suggests that the beneficial effects of thecoding mutations is independent of the promoter haplotype.

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

Defective IL7R expression in T-B+NK+ severe combinedimmunodeficiency. Puel A, Ziegler SF, Buckley RH, LeonardWJ: Nat Genet 1998, 20:394-397.• Significance: This excellent report provides the first demon-stration that human IL-7 is essential for T cell development butis dispensable for the development of B cells and natural killer(NK) cells.Findings: Impaired IL-7-receptor α-chain mRNA expressionwas found in two unrelated children with T– B+ NK+ severecombined immunodeficiency. One child was shown to be com-pound heterozygous for two null recessive IL-7-receptorα-chain gene (IL7R) mutations (a splice acceptor mutation anda non-sense mutation). In the second patient, disease-causingmutations were not identified in the coding region, implyingthat they are located in the regulatory regions of IL7R.

CancerSelected by Paul R WalkerUniversity Hospital Geneva, Geneva

Proto-oncogene PML controls genes devoted to MHCclass I antigen presentation. Zheng P, Guo Y, Niu Q, Levy D,Dyck JA, Sheiman LA, Liu Y: Nature 1998, 396:373-376.• Significance: In many tumours, there is inadequate expres-sion of MHC class I at the cell surface, rendering antitumourimmunity based on cytotoxic T lymphocytes (CTLs) ineffectual.

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This paper demonstrates that multiple antigen-presentationdefects can be caused by a dominant-negative mutation of theproto-oncogene PML. Findings: Recurring plasmocytoma J558 tumours arising in thepresence of strong antitumour immunity expressed no class I atthe cell surface and were resistant to CTL-mediated cytolysis.Little or no mRNA was detected for the transporter associatedwith antigen presentation (TAP)-1, TAP-2, low-molecular-weightpolypeptide (LMP)-2 or LMP-7 — gene products that are criticalfor antigen-presentation and for class I assembly. A cDNA clonewas identified that restored MHC class I expression; this corre-sponded to an isoform of the proto-oncogene PML, originallyidentified in acute promyelocytic leukemia but with no previouslydescribed function. A mutated PML exon encoding a truncatedprotein was found in class-I-negative sublines; this negativelyregulated the expression of the wild-type allele in transfectionexperiments. Conversely, overexpression of wild-type PML aug-mented class I expression in untransformed fibroblasts as wellas in tumour cell lines. These findings encourage a critical evalu-ation of the contribution of PML malfunction in tumour escapefrom the immune system.

Ex vivo staining of metastatic lymph nodes by class I majorhistocompatibility complex tetramers reveals high numbersof antigen-experienced tumor-specific cytolytic T lympho-cytes. Romero P, Dunbar PR, Valmori D, Pittet M, Ogg GS,Rimoldi D, Chen J-L, Liénard D, Cerottini J-C, Cerundolo V:J Exp Med 1998, 188:1641-1650.• Significance: Accurate assessment of tumour-specific CTLs,whether spontaneous or those induced by therapy, has been amajor hurdle in tumour immunology. Here — for the first time —CTLs specific for spontaneous human tumours arecharacterised directly ex vivo, making use of MHC-tetramers.In cancers for which CTL epitopes and MHC restriction ele-ments have been identified, the application and development ofthis technology will clearly be important in the monitoring ofantitumour immune responses as well as for sorting specificcells for subsequent adoptive immunotherapy.Findings: Lymphocytes from melanoma-infiltrated lymph nodesof HLA-A*0201+ patients were stained with fluorescentHLA-A2 tetramers synthesised around antigenic peptides fromeither tyrosinase or Melan-A/MART-1 (melanocyte specific)proteins. Tetramer-binding cells were CD8+ and CD45RO+

(corresponding to CTLs previously exposed to antigen) andthey exhibited specific cytotoxicity after in vitro expansion.Surprisingly high frequencies of specific CTLs were detectedin many patients (5–20-fold higher than calculated by limitingdilution assays), including patients with detectable tumours,raising questions about the efficacy of these cells in vivo.

Caspase 1-independant IL-1ββ release and inflammationinduced by the apoptosis inducer Fas ligand. Miwa K,Asano M, Horai R, Iwakura Y, Nagata S, Suda T: Nat Med1998, 4:1287-1292. • Significance: Overexpression of Fas ligand (CD95L) incertain experimental models (for cancer or transplantation) canbe accompanied by neutrophil infiltration. This paper defines anovel function of Fas ligand that may explain this phenomenon. Findings: Intraperitoneal implantion of MethA fibrosarcoma cellstransfected with a noncleavable modified Fas ligand (MAFL)induced a neutrophil-rich peritoneal infiltrate, accompanied byhigh levels of intraperitoneal IL-1β. In vitro studies, treating iso-lated peritoneal exudate cells with recombinant soluble Fas

ligand, suggested that Fas ligand induced the processing andrelease of IL-1β from neutrophils through caspase activation.Most of the neutrophils subsequently died from apoptosis,although apoptosis-resistant cells may conceivably arise withIL-1 exposure. The in vivo importance of IL-1 release (at least inthis anatomical site, with this transfected tumour line) wasdemonstrated in IL-1α/β-knockout mice, in which MAFL-inducedneutrophil infiltration was significantly impaired.

Regulation of the proinflammatory effects of Fas ligand(CD95L). Chen J-J, Sun Y, Nabel GJ: Science 1998,282:1714-1717.• Significance: The different consequences of Fas ligandexpression by different tumours or in different sites has not, todate, been adequately explained. In this study, transforminggrowth factor β (TGF-β) is shown to play a key role in inhibitingneutrophil activation by Fas ligand. Tumours expressing bothTGF-β and Fas ligand may thus be well equipped to escape anantitumour immune response. Findings: The colon carcinoma CT26 transfected with Fas ligand(CT26-CD95L) was rejected by neutrophils when injected subcu-taneously but survived in the anterior chamber of the eye, which isnaturally rich in TGF-β1. To determine whether TGF-β could modifytumorigenicity of CT26-CD95L, the tumour line was further trans-fected with a vector encoding active TGF-β1; thisdouble-transfectant grew progressively in the subcutaneous site.In vitro experiments to elucidate the mechanism showed that TGF-β1 suppressed Fas-ligand-induced p38 (mitogen-activated proteinkinase) activity in neutrophils, thereby reducing their cytotoxicity.

TransplantationSelected by Kathryn Wood and Andrew BushellJohn Radcliffe Hospital, Oxford

The effect of tolerance to noninherited maternal HLA anti-gens on the survival of renal transplants from sibling donors.Burlingham WJ, Grailer AP, Heisy DM, Claas FHJ, Norman D,Mohanakumar T, Brennan DC, Fijter DE, Van Gelder H, Pirsch Tet al.: N Engl J Med 1998, 339:1657-1664.• Significance: Continued improvements in immunosuppres-sive therapy have resulted in most kidney transplant centresreporting graft survival figures at 1 year of about 90%; however,such improvements have not resulted in correspondingincreases in long-term graft survival because of our inability tocontrol immune-mediated chronic rejection. Clearly, strategieswhich extend graft survival provide both benefit to the transplantrecipient and the possibility of increased understanding of theimmunological mechanisms that determine graft outcome. Findings: Previous reports have suggested that in transplantsbetween siblings where the donor and recipient are mismatchedfor one HLA haplotye there is a clear benefit if the graft donorexpresses maternal HLA antigens not expressed by the recipi-ent. The suggestion is that the developing foetus is exposed tothese noninherited maternal antigens (NIMAs) in utero and isthus unresponsive to the same antigens when expressed on thedonor organ. Burlingham et al. sought to address this possibilityin a multicentre retrospective study involving about 200 trans-plants. When graft survival was compared between donorsexpressing NIMAs or noninherited paternal antigens (NIPAs),there was a clear survival benefit in the NIMA group.

Control of neonatal tolerance to tissue antigens by peripheralT cell trafficking. Alferink J, Tafuri A, Vestweber D, Hallmann R,Hammerling GJ, Arnold B: Science 1998, 282:1338-1341.

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• Significance: Neonatal tolerance has been an area ofintense study since Medawar’s group first demonstrated thatexposure of the developing foetus to alloantigens could lead tostable, life-long tolerance. The use of anticlonotype monoclonalantibodies subsequently allowed several groups to show thatneonatal tolerance in normal animals depends to a large extenton clonal deletion of self-reactive T cells in the thymus;however, significant questions still remained about tolerance toperipheral antigens that are not expressed in the thymus. Thepaper of Alferink et al. indicates that the maturation state of thetissue bearing self-antigens may play an important role in thedevelopment of neonatal tolerance.Findings: Mice transgenic for the class I MHC antigen Kb,inserted under a keratin promoter, express Kb on skin ker-atinocytes. When crossed onto a Rag-2 background theresult is a cohort of Kb-positive, T-cell-negative recipients(2.4Ker-IVKb.Rag-2). At different ages, these mice werereconstituted with T-cell-depleted bone-marrow from theTCR-transgenic Des mouse (Des-TCR) whose T cellsexpress an anti-Kb TCR. The data suggest that neonatal tol-erance to antigens not expressed in the thymus depends onmigration of T cells (presumably very recent thymic emi-grants) into the tissues but that this only occurs during foetaland very early neonatal life. The finding that increasedaccess appears to be a function of the peripheral tissueitself is fascinating. It remains to be seen whether any facetsof this mechanism can be exploited in protocols intended toprovide true tolerance in clinical transplantation.

Atopic allergy and hypersensitivitySelected by Santa OnoSchepens Eye Research Institute, Cambridge, Massachusetts

LFA-1 interaction with ICAM-1 and ICAM-2 regulates Th2cytokine production. Salomon B, Bluestone JA: J Immunol1998, 161:5138-5142.• Significance: Interactions of the co-stimulatory moleculesand adhesion molecules CD28/B7 and LFA-1/ICAM areimportant for T cell activation. In this report, the relative contri-butions of these interactions on T cell proliferation and cytokineproduction are assessed in vitro using blocking antibodies. Findings: Blockade of either CD28–B7 or LFA-1–ICAM inter-actions partially inhibits T cell proliferation. Blocking of theCD28–B7 interaction inhibits Th2-type cytokine production,while blocking LFA-1–ICAM-1/ICAM-2 interactions results insignificant increases in Th2-type cytokine production. Thesedata suggest that the two different co-stimulatory pathwayshave opposing roles in Th2-cell development.

Generation of a novel stem cell factor-dependent mast cellprogenitor. Yuan Q, Gurish MF, Friend DS, Austen FK, BoyceJA: J Immunol 1998, 161:5143-5146.• Significance: Mast cell progenitors are derived from pluripo-tent bone-marrow stem cells. This paper describes the roles ofthree factors — stem cell factor (SCF), IL-6 and IL-10 — in mastcell development in vitro. Findings: In vitro differentiation of bone-marrow stem cells toprogenitor mast cells was achieved using the triad of cytokinesdescribed above. Upon differentiation, the progenitor mastcells exhibited IL-3-mediated mitogenic and maturationresponses. Three weeks after in vitro culture, the cells werec-kit-high Thy-1-low and were considered to be promastocytes.One week later, the progenitor mast cells expressed the IgE-receptor 1. These cells responded to SCF and IL-3 by

expressing mast cell carboxypeptidase A. These studies definedistinct roles for a panel of cytokines in mast cell development.

AutoimmunitySelected by Marc BonnevilleINSERM U 211, Institut de Biologie, Nantes

Prevention of acute allograft rejection by antibody targetingof TIRC7, a novel T cell membrane protein. Utku N, HeinemannT, Tullius SG, Bulwin GC, Beinke S, Blumberg RS, Beato F,Randall J, Kojima R, Busconi L et al.: Immunity 1998, 9:509-518.• Significance: This paper describes a novel T cell surfacemolecule playing a central role in T cell activation in vitro and invivo. This receptor may serve as a new target for modulation ofcellular immune responses.Findings: A new gene, TIRC7, encoding a membrane proteinwhich is differentially expressed in alloactivated human T cellswas identified by differential-display reverse-transcriptase poly-merase-chain reaction analysis. Antibodies against TIRC7inhibited T cell proliferation and IL-2/IFN-γ production, but notIL-4 production, thus suggesting a selective inhibitory effect onthe Th1 subset. An anti-TIRC7 antibody cross-reacting againsta rat homolog inhibited rat alloresponses in vitro and pro-longed kidney allograft survival in vivo.

Major histocompatibility complex class I-restricted T cells arerequired for all but the end stages of diabetes developmentin nonobese diabetic mice and use a prevalent T cell receptorαα chain gene rearrangement. DiLorenzo TP, Graser RT, Ono T,Christianson GJ, Chapman HD, Roopenian DC, Nathenson SG,Serreze DV: Proc Natl Acad Sci USA 1998, 95:12538-12543.• Significance: The authors provide the first strong evidencethat diabetogenic CD8+ T cells participating in the early phaseof islet β cell destruction recognize a common MHC-class-I-restricted antigen on pancreatic β cells.Findings: This study shows by adoptive transfer experimentsthat class-I-dependent T cells are critical to all but the finalstages of diabetes development in NOD mice. CD8+ T cellsisolated from the earliest insulitic lesions were propagated;they were cytotoxic to NOD islet cells, restricted to H-2Kd andused a prevalent TCR α−chain gene rearrangement bearingrecurrent junctional motifs.

Thymic lymphoproliferative disease after successful cor-rection of CD40 ligand deficiency by gene transfer in mice.Brown MP, Topham DJ, Sangster MY, Zhao J, Flynn KJ, SurmanSL, Woodland DL, Doherty PC, Farr AG, Pattengale PK,Brenner MK: Nat Med 1998, 4:1253-1260.• Significance: This important study shows the limitations ofgene replacement therapy, which may prove inappropriate fordiseases involving tightly regulated genes controlling cell prolif-eration processes.Findings: Interactions between CD40 and its ligand(CD40L) are central to induction and regulation of immuneresponses. Accordingly, inherited deficiency of CD40L isassociated with severe immune impairment that is character-ized by failure of immunoglobulin isotype-switching anddefects of cell-mediated immunity. Restoration of normal cel-lular and humoral responses in CD40L-deficient mice wasachieved by injecting bone-marrow cells transduced with aretroviral vector containing the CD40L gene. In the long term,12 out of 19 injected mice developed T cell lymphoprolifera-tive disorders ranging from lymphocytosis to overt T celllymphoblastic lymphomas. This suggests that constitutive

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(instead of regulated) expression of CD40L can produce dys-regulated T cell proliferation, presumably through aberrantCD40–CD40L interactions.

Control of neonatal tolerance to tissue antigens by periph-eral T cell trafficking. Alferink J, Tafuri A, Vestweber D,Hallmann R, Hämmerling GJ, Arnold B: Science 1998,282:1338-1341.•• Significance: This is the first indication that T cell traffickingthrough nonlymphoid tissues is crucial for the establishment ofself tolerance to sessile extrathymic antigens.

Findings: This study shows that neonatal tolerance to skin-restricted antigens does not depend on an intrinsic property ofT cells leaving the neonatal thymus but, instead, on the matura-tional stage of the peripheral tissue. In support of this, firstly,neonatal but not adult skin is accessible to naive CD8+ T cells;secondly, age-matched thymic emigrants are tolerized to askin-expressed antigen only during a neonatal period but notduring adulthood; and, thirdly, neonatal tolerance induction isprevented by injections of antibodies to E- and P-selectin —which block interactions between T cells and endothelia andthe subsequent migration of T cells into the skin.

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