The CD38/NAD/SIRTUIN1/EZH2 Axis Mitigates Cytotoxic CD8 T Cell Function and Identifies Patients with SLE Prone to Infections.
The CD38/NAD/SIRTUIN1/EZH2 Axis Mitigates Cytotoxic CD8 T Cell Function and Identifies Patients with SLE Prone to Infections.
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DOI：
10.1016/j.celrep.2019.12.014
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发表时间：
2020-01-07
期刊：
影响因子：
8.8
通讯作者：
Tsokos GC
中科院分区：
文献类型：
--
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
系统性红斑狼疮（SLE）患者经常感染，导致显著的发病率和死亡率。SLE患者的T细胞毒性反应降低，但其分子机制尚不清楚。我们发现一个扩大的CD 8 CD 38 high T细胞亚群的患者感染率增加的一个亚组。来自健康受试者和SLE患者的CD 8-CD 38-high T细胞显示出细胞毒性能力、脱颗粒、颗粒酶A和B以及穿孔素的表达降低。关键的细胞毒性相关转录因子T-bet、RUNX 3和EOMES在CD 8 CD 38 high T细胞中减少。CD 38通过抑制去乙酰化酶Sirtuin 1导致乙酰化EZH 2增加。乙酰化的EZH 2抑制RUNX 3表达，而EZH 2的抑制恢复CD 8 T细胞的细胞毒性应答。我们认为高水平的CD 38导致SLE患者CD 8 T细胞介导的细胞毒性降低，感染倾向增加，这一过程可以逆转。Katsuyama等发现SLE患者中扩增的CD 8 CD 38 high T细胞群与感染有关。CD 8 CD 38 high T细胞通过NAD+/Sirtuin 1/EZH 2途径抑制相关分子的表达，从而显示出降低的细胞毒性能力。EZH 2抑制剂增加细胞毒性，提供了减轻SLE感染率的方法。
Patients with systemic lupus erythematosus (SLE) suffer frequent infections that account for significant morbidity and mortality. T cell cytotoxic responses are decreased in patients with SLE, yet the responsible molecular events are largely unknown. We find an expanded CD8CD38high T cell subset in a sub-group of patients with increased rates of infections. CD8CD38high T cells from healthy subjects and patients with SLE display decreased cytotoxic capacity, degranulation, and expression of granzymes A and B and perforin. The key cytotoxicity-related transcription factors T-bet, RUNX3, and EOMES are decreased in CD8CD38high T cells. CD38 leads to increased acetylated EZH2 through inhibition of the deacetylase Sirtuin1. Acetylated EZH2 represses RUNX3 expression, whereas inhibition of EZH2 restores CD8 T cell cytotoxic responses. We propose that high levels of CD38 lead to decreased CD8 T cell-mediated cytotoxicity and increased propensity to infections in patients with SLE, a process that can be reversed pharmacologically. Katsuyama et al. find that an expanded CD8CD38high T cell population in SLE patients is linked to infections. CD8CD38high T cells display decreased cytotoxic capacity by suppressing the expression of related molecules through an NAD+/Sirtuin1/EZH2 pathway. EZH2 inhibitors increase cytotoxicity offering a means to mitigate infection rates in SLE.
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DOI：
10.1002/art.40038
发表时间：
2017-05
期刊：
Arthritis & rheumatology (Hoboken, N.J.)
影响因子：
--
作者：
Comte D;Karampetsou MP;Yoshida N;Kis-Toth K;Kyttaris VC;Tsokos GC
通讯作者：
Tsokos GC
影响因子：
2.7
作者：
Didion JP;Martin M;Collins FS
通讯作者：
Collins FS
影响因子：
6.7
作者：
Buggert M;Tauriainen J;Yamamoto T;Frederiksen J;Ivarsson MA;Michaëlsson J;Lund O;Hejdeman B;Jansson M;Sönnerborg A;Koup RA;Betts MR;Karlsson AC
通讯作者：
Karlsson AC
影响因子：
2.6
作者：
Feng, M.;Zhang, S. L.;Luo, J.
通讯作者：
Luo, J.
影响因子：
29
作者：
Chatterjee S;Daenthanasanmak A;Chakraborty P;Wyatt MW;Dhar P;Selvam SP;Fu J;Zhang J;Nguyen H;Kang I;Toth K;Al-Homrani M;Husain M;Beeson G;Ball L;Helke K;Husain S;Garrett-Mayer E;Hardiman G;Mehrotra M;Nishimura MI;Beeson CC;Bupp MG;Wu J;Ogretmen B;Paulos CM;Rathmell J;Yu XZ;Mehrotra S
通讯作者：
Mehrotra S