Counter-regulation of regulatory T cells by autoreactive CD8+ T cells in rheumatoid arthritis
Counter-regulation of regulatory T cells by autoreactive CD8+ T cells in rheumatoid arthritis
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DOI：
10.1016/j.jaut.2019.02.001
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发表时间：
2019-05-01
影响因子：
12.8
通讯作者：
Barnaba, Vincenzo
中科院分区：
文献类型：
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作者：
Cammarata, Ilenia;Martire, Carmela;Barnaba, Vincenzo
自身反应性T细胞逃避外周耐受从而导致人类自身免疫性疾病的机制仍然是一个悬而未决的问题。在这里，我们证明，在类风湿性关节炎（RA）患者中，自身反应性多功能CD8（+）T细胞以高亲和力识别自身抗原（即波形蛋白、肌动蛋白细胞质1或非肌肉肌球蛋白重链9表位），通过杀死Tregs来反向调节Tregs，在类风湿性关节炎（RA）患者中的比例一致。事实上，这些CD8(+) T细胞表达效应(eff)细胞的表型和基因谱，并且在抗原特异性激活后，在体外以NKG2D依赖性旁观者方式间接杀死Tregs。该数据为这一发现提供了机制基础，表明在体内稳态和后续研究中，AE特异性(CD107a(+)) CD8(+) T杀伤细胞与疾病活动评分直接相关，与激活的Tregs的百分比成反比。此外，体内炎症滑膜组织的多重免疫荧光成像分析表明，大量的CD8(+) T细胞表达颗粒酶-B并选择性地接触FOXP3(+) Tregs，其中一些处于凋亡状态，因此验证了CD8(+) Teff细胞可以通过杀死炎症组织内邻近的Treg来抵消它们。或者，不同患者亚群的疾病活动评分与自身反应性低亲合力、部分激活的（pa）CD8（+）T细胞的特殊亚群的扩张相关，尽管它们保留了传统的幼稚（N）表型，但产生高水平的肿瘤坏死因子（TNF）-α并表现出渐进激活状态的基因表达特征。 Tregs 与体内这种自身反应性（低亲合力）paCD8(+) TN 细胞亚群的扩增直接相关，并且在体外有效地控制它们的分化而不是增殖。有趣的是，自身反应性高亲和力CD8(+) Teff细胞或低亲和力paCD8(+) TN细胞分别在对TNF-α抑制剂治疗无反应或有反应的RA患者中显着扩增。这些数据提供了此类机制在 RA 进展和治疗中先前未描述的作用的证据。
The mechanisms whereby autoreactive T cells escape peripheral tolerance establishing thus autoimmune diseases in humans remain an unresolved question. Here, we demonstrate that autoreactive polyfunctional CD8(+) T cells recognizing self-antigens (i.e., vimentin, actin cytoplasmic 1, or non-muscle myosin heavy chain 9 epitopes) with high avidity, counter-regulate Tregs by killing them, in a consistent percentage of rheumatoid arthritis (RA) patients. Indeed, these CD8(+) T cells express a phenotype and gene profile of effector (eff) cells and, upon antigen-specific activation, kill Tregs indirectly in an NKG2D-dependent bystander fashion in vitro. This data provides a mechanistic basis for the finding showing that AE-specific (CD107a(+)) CD8(+) T killer cells correlate, directly with the disease activity score, and inversely with the percentage of activated Tregs, in both steady state and follow-up studies in vivo. In addition, multiplex immunofluorescence imaging analyses of inflamed synovial tissues in vivo show that a remarkable number of CD8(+) T cells express granzyme-B and selectively contact FOXP3(+) Tregs, some of which are in an apoptotic state, validating hence the possibility that CD8(+) Teff cells can counteract neighboring Tregs within inflamed tissues, by killing them. Alternatively, the disease activity score of a different subset of patients is correlated with the expansion of a peculiar subpopulation of autoreactive low avidity, partially-activated (pa)CD8(+) T cells that, despite they conserve the conventional naive (N) phenotype, produce high levels of tumor necrosis factor (TNF)-alpha and exhibit a gene expression signature of a progressive activation state. Tregs directly correlate with the expansion of this autoreactive (low avidity) paCD8(+) TN cell subset in vivo, and efficiently control their differentiation rather their proliferation in vitro. Interestingly, auto-reactive high avidity CD8(+) Teff cells or low avidity paCD8(+) TN cells are significantly expanded in RA patients who would become non-responders or patients who would become responders to TNF-alpha inhibitor therapy, respectively. These data provide evidence of a previously undescribed role of such mechanisms in the progression and therapy of RA.