T cells escape deletion
1
HIGHLIGHTS NATURE REVIEWS | IMMUNOLOGY VOLUME 4 | JANUARY 2004 | 5 Defects in thymic T-cell selection have long been suspected to lead to autoimmunity and now, Shimon Sakaguchi and colleagues describe a mouse model of autoimmune arthritis in which disease is caused by a single point mutation in the ζ-chain-associated protein 70 (Zap70) gene, altering the threshold of T-cell receptor (TCR) signalling and enabling autoreactive T cells to avoid deletion. Sakaguchi et al. derived the SKG strain of mice from BALB/c animals and observed that they spontaneously developed a chronic arthritis that resembles rheumatoid arthritis in humans. Initial joint swelling was limited to finger joints of the forepaws, but progressed to the hindpaws, wrists and ankles and was accompanied by high titres of rheumatoid factor. Immunohisto- chemistry of the swollen joints revealed a marked cellular infiltration that included CD4 + T cells, and these cells were shown to mediate disease as they induced arthritis after transfer to T-cell-deficient recipients. The Skg locus was mapped to a region of chromosome 1 that is known to include the Zap70 gene and further analysis identified a single nucleotide substitution in Zap70 of SKG mice, which altered the initial amino-acid residue of the carboxy- terminal Src homology 2 (SH2) domain. Transgenic expression of normal human ZAP70 by SKG mice prevented the development of arthritis, confirming the mutation as the cause of disease. SKG T cells were shown to have a diminished proliferative response to specific peptide as well as poly- clonal stimulation with CD3-specific antibodies, presumably as a result of the observed reduction in phospho- rylation of key signalling molecules and the inability of Zap70 to associate with TCR-ζ. Transgenic T cells expressing an MHC class-I-restricted TCR specific for the male H-Y antigen (HY-TCR) are efficiently selected in female mice, but are negatively selected in males. However, the authors observed that after crossing these TCR-transgenic mice onto a homozygous SKG back- ground, positive selection of HY- TCR + CD8 + T cells now occurred efficiently in male mice, indicating that the Skg mutation allows positive selection of T cells that are otherwise negatively selected. Further evidence for this was provided by the observa- tion that SKG mice expressing an MHC class-II-restricted TCR have an increased population of transgenic- TCR low CD4 + T cells that express an endogenous TCR-α chain compared with wild-type TCR-transgenic mice. These results provide evidence that genetic mutations affecting the TCR-signalling pathway in such a way as to disrupt T-cell selection can cause autoimmunity in mice, and the authors suggest that similar muta- tions might prove to be important in the development of rheumatoid arthritis in some human patients. Karen Honey References and links ORIGINAL RESEARCH PAPER Sakaguchi, N. et al. Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice. Nature 426, 454–460 (2003) IN BRIEF HSP70 promotes antigen-presenting cell function and converts T-cell tolerance to autoimmunity in vivo. Millar, D. G. et al. Nature Med. 16 November 2003 (doi:10.1038/nm962) Here, Millar et al. show that administration of HSP70 increases the stimulatory capacity of antigen-presenting cells (APCs) in vivo. Mice engineered to express the lymphocytic choriomeningitis virus glycoprotein (LCMV-GP) in pancreatic β-cells and in which CD8 + T cells are specific for LCMV-GP are tolerant when administered the immunodominant LCMV-GP-derived epitope gp33. HSP70 converts tolerance to autoimmunity when co-administered with gp33, rapidly inducing diabetes. HSP70 did not increase the expression of MHC class II molecules or CD80/CD86 by APCs, but its ability to induce diabetes was dependent on CD4 + T-cell help and CD40 expression by APCs. The authors, therefore, suggest that HSP70 partially activates APCs, but subsequent CD40 ligation is required for full activation and the onset of diabetes. A conserved signal-responsive sequence mediates activation-induced alternative splicing of CD45. Rothrock, C. et al. Mol. Cell 12, 1317–1324 (2003) Alterative splicing generates the distinct CD45 isoforms expressed by naive and activated T cells. In this paper, Rothrock et al. identify a consensus sequence — the activation-responsive sequence (ARS) — that is required for the exclusion of exons 4, 5 and 6 from CD45 after stimulation with phorbol 12-myristate 13-acetate (PMA). The ARS within exon 4 was mapped and when compared with exons 5 and 6 for regions of sequence homology, a conserved imperfect repeat sequence was observed. ARS-homology regions were found and shown to mediate PMA-induced alternative splicing in other PMA-regulated genes, including cytotoxic T lymphocyte antigen 4 (CTLA4), Agrin (AGRN) and FYN . These studies indicate that a common pathway might regulate activation-induced alternative splicing of a large number of diverse genes. Use of a small molecule CCR5 inhibitor in macaques to treat simian immunodeficiency virus infection or prevent simian–human immunodeficiency virus infection. Veazey, R. S. et al . J. Exp. Med. 198, 1551–1562 (2003) Absence of the chemokine receptor CCR5 protects against HIV infection, and therapies for HIV based on CCR5-specific antibodies are being developed. In this study, the effects of a CCR5-specific receptor agonist CMPD167 on established simian immunodeficiency virus (SIV) infection were investigated. CMPD167 was shown to have antiviral activity against SIVmac251 and SIVB670 replication in vivo, resulting in marked decreases in plasma viraemia in six rhesus macaques, which was maintained in three animals.Vaginal administration of gel-formulated CMPD167 reduced the extent of viraemia after infection with SHIV-162P4, but was unable to prevent vaginal transmission. HIV GENE REGULATION AUTOIMMUNITY T cells escape deletion AUTOIMMUNITY
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T cells escape deletion
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H I G H L I G H T S
NATURE REVIEWS | IMMUNOLOGY VOLUME 4 | JANUARY 2004 | 5
Defects in thymic T-cell selectionhave long been suspected to lead toautoimmunity and now, ShimonSakaguchi and colleagues describea mouse model of autoimmunearthritis in which disease is causedby a single point mutation in the ζ-chain-associated protein 70(Zap70) gene, altering the thresholdof T-cell receptor (TCR) signallingand enabling autoreactive T cells toavoid deletion.
Sakaguchi et al. derived theSKG strain of mice fromBALB/c animals and observed thatthey spontaneously developed achronic arthritis that resemblesrheumatoid arthritis in humans. Initialjoint swelling was limited to fingerjoints of the forepaws, but progressedto the hindpaws, wrists and ankles andwas accompanied by high titres ofrheumatoid factor. Immunohisto-chemistry of the swollen jointsrevealed a marked cellular infiltrationthat included CD4+ T cells, and thesecells were shown to mediate disease asthey induced arthritis after transfer toT-cell-deficient recipients.
The Skg locus was mapped to aregion of chromosome 1 that isknown to include the Zap70 geneand further analysis identified a singlenucleotide substitution in Zap70 ofSKG mice, which altered the initialamino-acid residue of the carboxy-terminal Src homology 2 (SH2)domain. Transgenic expression ofnormal human ZAP70 by SKG miceprevented the development ofarthritis, confirming the mutationas the cause of disease.
SKG T cells were shown to havea diminished proliferative responseto specific peptide as well as poly-clonal stimulation with CD3-specificantibodies, presumably as a result ofthe observed reduction in phospho-rylation of key signalling moleculesand the inability of Zap70 to associatewith TCR-ζ.
Transgenic T cells expressing anMHC class-I-restricted TCR specificfor the male H-Y antigen (HY-TCR)are efficiently selected in female mice,
but are negatively selected in males.However, the authors observed thatafter crossing these TCR-transgenicmice onto a homozygous SKG back-ground, positive selection of HY-TCR+CD8+ T cells now occurred efficiently in male mice, indicatingthat the Skg mutation allows positiveselection of T cells that are otherwisenegatively selected. Further evidencefor this was provided by the observa-tion that SKG mice expressing anMHC class-II-restricted TCR have anincreased population of transgenic-TCRlow CD4+ T cells that express anendogenous TCR-α chain comparedwith wild-type TCR-transgenic mice.
These results provide evidencethat genetic mutations affecting theTCR-signalling pathway in such away as to disrupt T-cell selection cancause autoimmunity in mice, and theauthors suggest that similar muta-tions might prove to be important inthe development of rheumatoidarthritis in some human patients.
Karen Honey
References and linksORIGINAL RESEARCH PAPER Sakaguchi, N.et al. Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causesautoimmune arthritis in mice. Nature 426,454–460 (2003)
IN BRIEF
HSP70 promotes antigen-presenting cell function andconverts T-cell tolerance to autoimmunity in vivo.Millar, D. G. et al. Nature Med. 16 November 2003 (doi:10.1038/nm962)
Here, Millar et al. show that administration of HSP70 increases thestimulatory capacity of antigen-presenting cells (APCs) in vivo.Mice engineered to express the lymphocytic choriomeningitis virusglycoprotein (LCMV-GP) in pancreatic β-cells and in which CD8+
T cells are specific for LCMV-GP are tolerant when administeredthe immunodominant LCMV-GP-derived epitope gp33. HSP70converts tolerance to autoimmunity when co-administered withgp33, rapidly inducing diabetes. HSP70 did not increase theexpression of MHC class II molecules or CD80/CD86 by APCs, butits ability to induce diabetes was dependent on CD4+ T-cell helpand CD40 expression by APCs. The authors, therefore, suggest thatHSP70 partially activates APCs, but subsequent CD40 ligation isrequired for full activation and the onset of diabetes.
A conserved signal-responsive sequence mediatesactivation-induced alternative splicing of CD45.Rothrock, C. et al. Mol. Cell 12, 1317–1324 (2003)
Alterative splicing generates the distinct CD45 isoforms expressedby naive and activated T cells. In this paper, Rothrock et al. identifya consensus sequence — the activation-responsive sequence (ARS)— that is required for the exclusion of exons 4, 5 and 6 from CD45after stimulation with phorbol 12-myristate 13-acetate (PMA). TheARS within exon 4 was mapped and when compared with exons 5and 6 for regions of sequence homology, a conserved imperfectrepeat sequence was observed. ARS-homology regions were foundand shown to mediate PMA-induced alternative splicing in otherPMA-regulated genes, including cytotoxic T lymphocyte antigen 4(CTLA4), Agrin (AGRN) and FYN . These studies indicate that acommon pathway might regulate activation-induced alternativesplicing of a large number of diverse genes.
Use of a small molecule CCR5 inhibitor in macaques totreat simian immunodeficiency virus infection or preventsimian–human immunodeficiency virus infection.Veazey, R. S. et al. J. Exp. Med. 198, 1551–1562 (2003)
Absence of the chemokine receptor CCR5 protects against HIV infection, and therapies for HIV based on CCR5-specificantibodies are being developed. In this study, the effects of a CCR5-specific receptor agonist CMPD167 on established simianimmunodeficiency virus (SIV) infection were investigated.CMPD167 was shown to have antiviral activity against SIVmac251and SIVB670 replication in vivo, resulting in marked decreases inplasma viraemia in six rhesus macaques, which was maintained inthree animals.Vaginal administration of gel-formulated CMPD167reduced the extent of viraemia after infection with SHIV-162P4,but was unable to prevent vaginal transmission.
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A U TO I M M U N I T YT cells escape deletion
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