Complementary HLH susceptibility factors converge on CD8 T-cell hyperactivation.
Complementary HLH susceptibility factors converge on CD8 T-cell hyperactivation.
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DOI：
10.1182/bloodadvances.2023010502
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发表时间：
2023-11-28
期刊：
影响因子：
7.5
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中科院分区：
文献类型：
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过量的IL-18和完全或部分穿孔蛋白缺乏共同驱动克隆性CD8 t细胞扩增。同时终端耗竭和效应程序定义CD8 t细胞过度活化。噬血细胞淋巴组织细胞增多症（HLH）和巨噬细胞激活综合征（MAS）是危及生命的高炎症综合征。家族性HLH是由颗粒介导的细胞毒性（如穿孔素缺乏）的遗传缺陷引起的。MAS与炎性小体激活的细胞因子白介素-18 （IL-18）的过度活性有关。虽然单独耐受，但具有双重易感性的小鼠（Prf1⁻/⁻18tg； DS）会自发地发生致命的过度炎症。我们假设，了解这些易感因子如何协同作用将揭示过度活化的CD8 T细胞的激活、功能和持久性的关键病理机制。在IL-18转基因（Il18tg）小鼠中，IL-18对CD8 T细胞的影响在病毒（淋巴细胞脉络丛脑膜炎病毒）而非先天（toll样受体9）触发后驱动MAS。在体外，CD8 T细胞也需要T细胞受体（TCR）刺激才能完全响应IL-18。IL-18诱导但穿孔素缺乏损害免疫调节再刺激诱导的细胞死亡（RICD）。与过度炎症相似，早在3周时，DS小鼠的脾脏、肝脏和骨髓中就出现了大量胸腺后寡克隆CD8 t细胞过度活化。这些细胞增加了增殖和干扰素γ的产生，与此形成对比的是与衰竭相关的受体和转录因子的表达增加。广谱抗生素和抗逆转录病毒药物未能改善该病。试图通过基因“固定”TCR抗原特异性，却证明了自发性HLH和过度激活的持久性，主要是在逃避TCR固定的T细胞上。因此，HLH的驱动因素可能优先作用于CD8 T细胞：IL-18放大RICD的激活和需求，而穿孔素提供关键的免疫调节。这些因子共同促进了CD8 t细胞的终端激活状态，结合了耗竭和效应功能的特点。因此，对过度炎症的易感性可能集中在CD8 t细胞过度激活的独特、无情和抗原依赖状态上。
Excess IL-18 and complete or partial perforin deficiency cooperate to drive clonal CD8 T-cell expansion. Concurrent terminal exhaustion and effector programs define CD8 T-cell hyperactivation. Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening hyperinflammatory syndromes. Familial HLH is caused by genetic impairment of granule-mediated cytotoxicity (eg, perforin deficiency). MAS is linked to excess activity of the inflammasome-activated cytokine interleukin-18 (IL-18). Though individually tolerated, mice with dual susceptibility (Prf1⁻/⁻Il18tg; DS) succumb to spontaneous, lethal hyperinflammation. We hypothesized that understanding how these susceptibility factors synergize would uncover key pathomechanisms in the activation, function, and persistence of hyperactivated CD8 T cells. In IL-18 transgenic (Il18tg) mice, IL-18 effects on CD8 T cells drove MAS after a viral (lymphocytic choriomeningitis virus), but not innate (toll like receptor 9), trigger. In vitro, CD8 T cells also required T-cell receptor (TCR) stimulation to fully respond to IL-18. IL-18 induced but perforin deficiency impaired immunoregulatory restimulation-induced cell death (RICD). Paralleling hyperinflammation, DS mice displayed massive postthymic oligoclonal CD8 T-cell hyperactivation in their spleens, livers, and bone marrow as early as 3 weeks. These cells increased proliferation and interferon gamma production, which contrasted with increased expression of receptors and transcription factors associated with exhaustion. Broad-spectrum antibiotics and antiretrovirals failed to ameliorate the disease. Attempting to genetically “fix” TCR antigen-specificity instead demonstrated the persistence of spontaneous HLH and hyperactivation, chiefly on T cells that had evaded TCR fixation. Thus, drivers of HLH may preferentially act on CD8 T cells: IL-18 amplifies activation and demand for RICD, whereas perforin supplies critical immunoregulation. Together, these factors promote a terminal CD8 T-cell activation state, combining features of exhaustion and effector function. Therefore, susceptibility to hyperinflammation may converge on a unique, unrelenting, and antigen-dependent state of CD8 T-cell hyperactivation.
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DOI：
10.4049/jimmunol.1000841
发表时间：
2010-09-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Mackerness KJ;Cox MA;Lilly LM;Weaver CT;Harrington LE;Zajac AJ
通讯作者：
Zajac AJ
影响因子：
5.2
作者：
FARQUHAR, JW;CLAIREAUX, AE
通讯作者：
CLAIREAUX, AE
影响因子：
13.5
作者：
Chapin, Catherine A.;Burn, Thomas;Alonso, Estella M.
通讯作者：
Alonso, Estella M.
DOI：
10.1073/pnas.1203543109
发表时间：
2012-06-19
影响因子：
11.1
作者：
Freeman, Bailey E.;Hammarlund, Erika;Slifka, Mark K.
通讯作者：
Slifka, Mark K.
影响因子：
30.5
作者：
Blackburn, Shawn D.;Shin, Haina;Haining, W. Nicholas;Zou, Tao;Workman, Creg J.;Polley, Antonio;Betts, Michael R.;Freeman, Gordon J.;Vignali, Dario A. A.;Wherry, E. John
通讯作者：
Wherry, E. John