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首页> 外文期刊>Nature >Dominant protection from HLA-linked autoimmunity by antigen-specific regulatory T cells
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Dominant protection from HLA-linked autoimmunity by antigen-specific regulatory T cells

机译：抗原特异性调节性T细胞对HLA连锁自身免疫的主要保护作用

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摘要

Susceptibility and protection against human autoimmune diseases, including type I diabetes, multiple sclerosis, and Goodpasture disease, is associated with particular human leukocyte antigen (HLA) alleles. However, the mechanisms underpinning such HLA-mediated effects on self-tolerance remain unclear. Here we investigate the molecular mechanism of Goodpasture disease, an HLA-linked autoimmune renal disorder characterized by an immunodominant CD4(+) T-cell self-epitope derived from the alpha 3 chain of type IV collagen (alpha 3(135-145))(1-4). While HLA-DR15 confers a markedly increased disease risk, the protective HLA-DR1 allele is dominantly protective in trans with HLA-DR15 (ref. 2). We show that autoreactive alpha 3(135-145)-specific T cells expand in patients with Goodpasture disease and, in alpha 3(135-145)-immunized HLA-DR15 transgenic mice, alpha 3(135-145)-specific T cells infiltrate the kidney and mice develop Goodpasture disease. HLA-DR15 and HLA-DR1 exhibit distinct peptide repertoires and binding preferences and present the alpha 3(135-145) epitope in different binding registers. HLA-DR15-alpha 3(135-145) tetramer(+) T cells in HLA-DR15 transgenic mice exhibit a conventional T-cell phenotype (T-conv) that secretes pro-inflammatory cytokines. In contrast, HLA-DR1-alpha 3(135-145) tetramer(+) T cells in HLA-DR1 and HLA-DR15/DR1 transgenic mice are predominantly CD4(+) Foxp3(+) regulatory T cells (T-reg cells) expressing tolerogenic cytokines. HLA-DR1-induced T-reg cells confer resistance to disease in HLA-DR15/DR1 transgenic mice. HLA-DR15(+) and HLA-DR1(+) healthy human donors display altered alpha 3(135-145)-specific T-cell antigen receptor usage, HLA-DR15-alpha 3(135-145) tetramer(+) Foxp3-T-conv and HLA-DR1-alpha 3(135-145) tetramer(+) Foxp3(+) CD25(hi)CD127(lo) T-reg dominant phenotypes. Moreover, patients with Goodpasture disease display a clonally expanded alpha 3(135-145)-specific CD4(+) T-cell repertoire. Accordingly, we provide a mechanistic basis for the dominantly protective effect of HLA in autoimmune disease, whereby HLA polymorphism shapes the relative abundance of self-epitope specific T-reg cells that leads to protection or causation of autoimmunity.
机译：对人类自身免疫性疾病（包括I型糖尿病，多发性硬化症和Goodpasture疾病）的敏感性和保护作用与特定的人类白细胞抗原（HLA）等位基因相关。但是，尚不清楚这种HLA介导的自我耐受作用的机制。在这里，我们研究了Goodpasture疾病的分子机制，该疾病是一种HLA连锁的自身免疫性肾脏疾病，其特征是来源于IV型胶原的alpha 3链的免疫显性CD4（+）T细胞自身表位（alpha 3（135-145））。 （1-4）。虽然HLA-DR15显着增加了疾病风险，但保护性HLA-DR1等位基因在反式中与HLA-DR15相比具有显着的保护作用（参考文献2）。我们显示自身反应性α3（135-145）特异性T细胞在Goodpasture疾病患者中扩展，并且在α3（135-145）免疫的HLA-DR15转基因小鼠中，α3（135-145）特异性T细胞渗入肾脏，小鼠发展为Goodpasture疾病。 HLA-DR15和HLA-DR1表现出截然不同的肽库和结合偏好，并在不同的结合寄存器中呈现出alpha 3（135-145）表位。 HLA-DR15转基因小鼠中的HLA-DR15-alpha 3（135-145）四聚体（+）T细胞显示出分泌促炎性细胞因子的常规T细胞表型（T-conv）。相反，HLA-DR1和HLA-DR15 / DR1转基因小鼠中的HLA-DR1-alpha 3（135-145）四聚体（+）T细胞主要是CD4（+）Foxp3（+）调节性T细胞（T-reg细胞） ）表达致耐受性细胞因子。 HLA-DR1诱导的T-reg细胞在HLA-DR15 / DR1转基因小鼠中赋予了对疾病的抗性。 HLA-DR15（+）和HLA-DR1（+）健康人类供体显示改变的alpha 3（135-145）特异性T细胞抗原受体使用，HLA-DR15 alpha 3（135-145）四聚体（+）Foxp3 -T-conv和HLA-DR1-alpha 3（135-145）四聚体（+）Foxp3（+）CD25（hi）CD127（lo）T-reg显性表型。此外，患有Goodpasture疾病的患者表现出克隆扩展的alpha 3（135-145）特异性CD4（+）T细胞库。因此，我们为HLA在自身免疫性疾病中占主导地位的保护作用提供了机械基础，由此HLA多态性影响了自身表位特异性T-reg细胞的相对丰度，从而导致自身免疫性的保护或起因。

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  • 来源
    《Nature》 |2017年第7653期|243-247|共5页
  • 作者

    Ooi Joshua D.; Petersen Jan; Tan Yu H.; Huynh Megan; Willett Zoe J.; Ramarathinam Sri H.; Eggenhuizen Peter J.; Loh Khai L.; Watson Katherine A.; Gan Poh Y.; Likhan Maliha A. A.; Dudek Nadine L.; Handel Andreas; Hudson Billy G.; Fugger Lars; Power David A.; Holt Stephen G.; Coates P. Toby; Gregersen Jon W.; Purcell Anthony W.; Holdsworth Stephen R.; La Gruta Nicole L.; Reid Hugh H.; Rossjohn Jamie; Kitching A. Richard;

  • 作者单位

    Monash Univ, Dept Med, Monash Med Ctr, Ctr Inflammatory Dis, Clayton, Vic 3168, Australia;

    Monash Univ, Infect & Immun Program, Biomed Discovery Inst, Clayton, Vic 3800, Australia|Monash Univ, Dept Biochem & Mol Biol, Biomed Discovery Inst, Clayton, Vic 3800, Australia|Monash Univ, Australian Res Council Ctr Excellence Adv Mol Ima, Clayton, Vic 3800, Australia;

    Monash Univ, Infect & Immun Program, Biomed Discovery Inst, Clayton, Vic 3800, Australia|Monash Univ, Dept Biochem & Mol Biol, Biomed Discovery Inst, Clayton, Vic 3800, Australia;

    Monash Univ, Dept Med, Monash Med Ctr, Ctr Inflammatory Dis, Clayton, Vic 3168, Australia;

    Monash Univ, Dept Med, Monash Med Ctr, Ctr Inflammatory Dis, Clayton, Vic 3168, Australia;

    Monash Univ, Infect & Immun Program, Biomed Discovery Inst, Clayton, Vic 3800, Australia|Monash Univ, Dept Biochem & Mol Biol, Biomed Discovery Inst, Clayton, Vic 3800, Australia;

    Monash Univ, Dept Med, Monash Med Ctr, Ctr Inflammatory Dis, Clayton, Vic 3168, Australia;

    Monash Univ, Infect & Immun Program, Biomed Discovery Inst, Clayton, Vic 3800, Australia|Monash Univ, Dept Biochem & Mol Biol, Biomed Discovery Inst, Clayton, Vic 3800, Australia;

    Univ Melbourne, Dept Microbiol & Immunol, Peter Doherty Inst Infect & Immun, Melbourne, Vic 3010, Australia|Walter & Eliza Hall Inst Med Res, Melbourne, Vic, Australia;

    Monash Univ, Dept Med, Monash Med Ctr, Ctr Inflammatory Dis, Clayton, Vic 3168, Australia;

    Monash Univ, Dept Med, Monash Med Ctr, Ctr Inflammatory Dis, Clayton, Vic 3168, Australia;

    Monash Univ, Infect & Immun Program, Biomed Discovery Inst, Clayton, Vic 3800, Australia|Monash Univ, Dept Biochem & Mol Biol, Biomed Discovery Inst, Clayton, Vic 3800, Australia;

    Univ Georgia, Coll Publ Hlth, Dept Epidemiol & Biostat, Athens, GA 30602 USA;

    Vanderbilt Univ, Med Ctr, Dept Med, Div Nephrol & Hypertens, Nashville, TN 37232 USA;

    Univ Oxford, Oxford Ctr Neuroinflammat, Nuffield Dept Clin Neurosci, John Radcliffe Hosp, Oxford OX3 9DS, England|Univ Oxford, MRC Human Immunol Unit, Weatherall Inst Mol Med, John Radcliffe Hosp, Oxford OX3 9DS, England;

    Austin Hlth, Dept Nephrol, Heidelberg, Vic 3084, Australia|Univ Melbourne, Dept Med, Melbourne, Vic 3010, Australia;

    Univ Melbourne, Dept Med, Melbourne, Vic 3010, Australia|Royal Melbourne Hosp, Dept Nephrol, Parkville, Vic 3050, Australia;

    Royal Adelaide Hosp, Cent Northern Adelaide Renal & Transplantat Serv, Adelaide, SA 5000, Australia;

    Viborg Reg Hosp, Dept Med, DK-8800 Viborg, Denmark;

    Monash Univ, Infect & Immun Program, Biomed Discovery Inst, Clayton, Vic 3800, Australia|Monash Univ, Dept Biochem & Mol Biol, Biomed Discovery Inst, Clayton, Vic 3800, Australia;

    Monash Univ, Dept Med, Monash Med Ctr, Ctr Inflammatory Dis, Clayton, Vic 3168, Australia|Monash Hlth, Dept Nephrol, Clayton, Vic 3168, Australia;

    Monash Univ, Infect & Immun Program, Biomed Discovery Inst, Clayton, Vic 3800, Australia|Monash Univ, Dept Biochem & Mol Biol, Biomed Discovery Inst, Clayton, Vic 3800, Australia|Univ Melbourne, Dept Microbiol & Immunol, Peter Doherty Inst Infect & Immun, Melbourne, Vic 3010, Australia;

    Monash Univ, Infect & Immun Program, Biomed Discovery Inst, Clayton, Vic 3800, Australia|Monash Univ, Dept Biochem & Mol Biol, Biomed Discovery Inst, Clayton, Vic 3800, Australia|Monash Univ, Australian Res Council Ctr Excellence Adv Mol Ima, Clayton, Vic 3800, Australia;

    Monash Univ, Infect & Immun Program, Biomed Discovery Inst, Clayton, Vic 3800, Australia|Monash Univ, Dept Biochem & Mol Biol, Biomed Discovery Inst, Clayton, Vic 3800, Australia|Monash Univ, Australian Res Council Ctr Excellence Adv Mol Ima, Clayton, Vic 3800, Australia|Cardiff Univ, Inst Infect & Immun, Sch Med, Heath Pk, Cardiff CF14 4XN, S Glam, Wales;

    Monash Univ, Dept Med, Monash Med Ctr, Ctr Inflammatory Dis, Clayton, Vic 3168, Australia|Monash Hlth, Dept Nephrol, Clayton, Vic 3168, Australia|Monash Univ, NHMRC Ctr Personalised Immunol, Clayton, Vic 3168, Australia|Monash Hlth, Dept Pediat Nephrol, Clayton, Vic 3168, Australia;

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