Trisomy 21 dysregulates T cell lineages toward an autoimmunity-prone state associated with interferon hyperactivity
Trisomy 21 dysregulates T cell lineages toward an autoimmunity-prone state associated with interferon hyperactivity
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DOI：
10.1073/pnas.1908129116
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发表时间：
2019-11-26
影响因子：
11.1
通讯作者：
Espinosa, Joaquin M.
中科院分区：
文献类型：
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作者：
Araya, Paula;Waugh, Katherine A.;Espinosa, Joaquin M.
21三体（T21）导致唐氏综合征（DS），一种以自身免疫性疾病的高患病率为特征的病症。然而，驱动这种表型的分子和细胞机制仍不清楚。建立在我们以前的发现，T细胞从人与DS显示干扰素（IFN）刺激基因的表达增加，我们已经完成了全面表征的外周T细胞区室在成人与DS与自身免疫性疾病。来自患有DS的成人的CD 8 + T细胞耗尽幼稚亚群并富集分化亚群，表达更高水平的活化和衰老标志物（例如，IFN-γ、粒酶B、PD-1、KLRG 1），并过度产生与自身免疫相关的细胞因子（例如，TNF-α）。常规的CD 4 + T细胞显示出增加的分化、向Th 1和Th 1/17状态的极化以及自身免疫相关细胞因子IL-17 A和IL-22的过度产生。血浆细胞因子分析证实多种自身免疫相关细胞因子（例如，TNF-α、IL-17 A-D、IL-22），与自身免疫诊断无关。尽管T21在DS中更丰富，但功能测定显示，具有T21的CD 8+和CD 4+效应T细胞对Treg介导的抑制具有抗性，无论Treg核型如何。白色血细胞和T细胞的转录组分析揭示了与IFN活性亢进正相关的T细胞分化和活化的强烈特征。最后，8个IFN-诱导的磷酸化表位的质谱分析表明，具有T21的T细胞亚群显示出基础IFN信号传导水平升高和对IFN-α刺激的超敏反应。因此，这些结果表明与IFN活性亢进相关的T细胞失调是DS中自身免疫的一个因素。
Trisomy 21 (T21) causes Down syndrome (DS), a condition characterized by high prevalence of autoimmune disorders. However, the molecular and cellular mechanisms driving this phenotype remain unclear. Building upon our previous finding that T cells from people with DS show increased expression of interferon (IFN)stimulated genes, we have completed a comprehensive characterization of the peripheral T cell compartment in adults with DS with and without autoimmune conditions. CD8+ T cells from adults with DS are depleted of naive subsets and enriched for differentiated subsets, express higher levels of markers of activation and senescence (e.g., IFN-gamma, Granzyme B, PD-1, KLRG1), and overproduce cytokines tied to autoimmunity (e.g., TNF-alpha). Conventional CD4+ T cells display increased differentiation, polarization toward the Th1 and Th1/17 states, and overproduction of the autoimmunity-related cytokines IL-17A and IL-22. Plasma cytokine analysis confirms elevation of multiple autoimmunity-related cytokines (e.g., TNF-alpha, IL17A-D, IL-22) in people with DS, independent of diagnosis of autoimmunity. Although Tregs are more abundant in DS, functional assays show that CD8+ and CD4+ effector T cells with T21 are resistant to Treg-mediated suppression, regardless of Treg karyotype. Transcriptome analysis of white blood cells and T cells reveals strong signatures of T cell differentiation and activation that correlate positively with IFN hyperactivity. Finally, mass cytometry analysis of 8 IFN-inducible phosphoepitopes demonstrates that T cell subsets with T21 show elevated levels of basal IFN signaling and hypersensitivity to IFN-alpha stimulation. Therefore, these results point to T cell dysregulation associated with IFN hyperactivity as a contributor to autoimmunity in DS.