Type I interferons affect the metabolic fitness of CD8(+) T cells from patients with systemic lupus erythematosus.
Type I interferons affect the metabolic fitness of CD8(+) T cells from patients with systemic lupus erythematosus.
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DOI：
10.1038/s41467-021-22312-y
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发表时间：
2021-03-31
影响因子：
16.6
通讯作者：
Botto M
中科院分区：
文献类型：
--
作者：
Buang N;Tapeng L;Gray V;Sardini A;Whilding C;Lightstone L;Cairns TD;Pickering MC;Behmoaras J;Ling GS;Botto M
大多数系统性红斑狼疮（SLE）患者具有高表达的I型IFN刺激基因。线粒体异常也有报道，但I型IFN暴露对这些变化的贡献尚不清楚。在此，我们通过对CD 4+和CD 8 + T细胞的转录组学分析，显示IFN-高水平患者中IFN-α衍生基因和IFN-α相关代谢途径的下调。来自这些患者的CD 8 + T细胞具有增大的线粒体和较低的备用呼吸能力，这与在用TCR刺激再激发时增加的细胞死亡相关。这些线粒体异常可以通过将来自健康志愿者的CD 8 + T细胞暴露于I型IFN和TCR刺激来表型复制。这些“SLE样”病症机械地增加了CD 8 + T细胞NAD+消耗，导致线粒体呼吸受损和细胞活力降低，这两者都可以通过NAD+补充来纠正。我们的数据表明，I型干扰素暴露有助于SLE的发病机制，通过促进CD 8 + T细胞死亡，通过代谢重新布线。狼疮发病机制与高1型干扰素刺激基因（ISG）表达有关。在这里，作者将狼疮性肾炎患者的CD 8 + T细胞中的ISG表达与异常线粒体功能相关联，暗示发病机制中NAD消耗增加和细胞活力降低。
The majority of patients with systemic lupus erythematosus (SLE) have high expression of type I IFN-stimulated genes. Mitochondrial abnormalities have also been reported, but the contribution of type I IFN exposure to these changes is unknown. Here, we show downregulation of mitochondria-derived genes and mitochondria-associated metabolic pathways in IFN-High patients from transcriptomic analysis of CD4+ and CD8+ T cells. CD8+ T cells from these patients have enlarged mitochondria and lower spare respiratory capacity associated with increased cell death upon rechallenge with TCR stimulation. These mitochondrial abnormalities can be phenocopied by exposing CD8+ T cells from healthy volunteers to type I IFN and TCR stimulation. Mechanistically these ‘SLE-like’ conditions increase CD8+ T cell NAD+ consumption resulting in impaired mitochondrial respiration and reduced cell viability, both of which can be rectified by NAD+ supplementation. Our data suggest that type I IFN exposure contributes to SLE pathogenesis by promoting CD8+ T cell death via metabolic rewiring. Lupus pathogenesis is associated with high type 1 interferon stimulated gene (ISG) expression. Here, the authors correlate ISG expression in CD8+ T cells from lupus nephritis patients with abnormal mitochondrial function, implicating increased NAD consumption and reduced cell viability in the pathogenesis.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
13.3
作者：
Chiche, Laurent;Jourde-Chiche, Noemie;Whalen, Elizabeth;Presnell, Scott;Gersuk, Vivian;Dang, Kristen;Anguiano, Esperanza;Quinn, Charlie;Burtey, Stephane;Berland, Yvon;Kaplanski, Gilles;Harle, Jean-Robert;Pascual, Virginia;Chaussabel, Damien
通讯作者：
Chaussabel, Damien
DOI：
10.1084/jem.20151876
发表时间：
2016-05-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Caielli S;Athale S;Domic B;Murat E;Chandra M;Banchereau R;Baisch J;Phelps K;Clayton S;Gong M;Wright T;Punaro M;Palucka K;Guiducci C;Banchereau J;Pascual V
通讯作者：
Pascual V
影响因子：
--
作者：
Couzi, Lionel;Merville, Pierre;Blanco, Patrick
通讯作者：
Blanco, Patrick
影响因子：
8.8
作者：
Katsuyama E;Suarez-Fueyo A;Bradley SJ;Mizui M;Marin AV;Mulki L;Krishfield S;Malavasi F;Yoon J;Sui SJH;Kyttaris VC;Tsokos GC
通讯作者：
Tsokos GC