Role of the Coinhibitory Receptor Cytotoxic T Lymphocyte Antigen-4 on Apoptosis-Prone CD8 T Cells in Persistent Hepatitis B Virus Infection
Role of the Coinhibitory Receptor Cytotoxic T Lymphocyte Antigen-4 on Apoptosis-Prone CD8 T Cells in Persistent Hepatitis B Virus Infection
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DOI：
10.1002/hep.24249
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发表时间：
2011-05-01
期刊：
影响因子：
13.5
通讯作者：
Maini, Mala K.
中科院分区：
文献类型：
--
作者：
Schurich, Anna;Khanna, Pooja;Maini, Mala K.
已经提出过多的共抑制信号来驱动持续病毒感染的T细胞耗竭特征。在这项研究中，我们研究了共抑制受体细胞毒性T淋巴细胞抗原-4(CTLA-4)在慢性乙型肝炎病毒(CHB)感染中CD8 T细胞耐受中的作用。慢性乙型肝炎患者CD8T细胞表达共抑制受体CTLA-4的倾向增加，这与病毒载量有关。CTLA-4在那些具有最高水平促凋亡蛋白Bim的HBV特异性CD8 T细胞上上调，我们先前已经证明这参与了它们的过早磨损；取消CTLA-4介导的共抑制可以减少Bim的表达。对开始抗病毒治疗的CHB患者的纵向研究表明，HBVDNA抑制诱导了HBV特异性CD8T细胞的一过性重建，但不会重新编程他们的CTLA-4(Hi)Bim(Hi)耐受表型。阻断CTLA-4能够增加干扰素-伽马(干扰素-伽马)产生的乙肝病毒特异性CD8 T细胞在外周和肝内的扩张。CTLA-4或PD-L1阻断对抗乙肝病毒应答的挽救是非多余的。结论：CTLA-4由高表达Bim的HBV特异性CD8T细胞表达，并有助于驱动这种促凋亡表型。CTLA-4的阻断可以形成一种治疗方法，以调节这种异质性疾病中T细胞耗竭的不同模式。(《肝病》2011；53：1494-1503)
An excess of coinhibitory signals has been proposed to drive the T-cell exhaustion characteristic of persistent viral infections. In this study we examined the contribution of the coinhibitory receptor cytotoxic T lymphocyte antigen-4 (CTLA-4) to CD8 T cell tolerance in chronic hepatitis B virus (HBV) infection (CHB). CD8 T cells in patients with CHB have an increased propensity to express the coinhibitory receptor CTLA-4 and this correlates with viral load. CTLA-4 is up-regulated on those HBV-specific CD8 T cells with the highest levels of the proapoptotic protein Bim, which we have previously shown mediates their premature attrition; abrogation of CTLA-4-mediated coinhibition can reduce Bim expression. Longitudinal study of CHB patients beginning antiviral therapy reveals that HBV DNA suppression induces transient reconstitution of HBV-specific CD8 T cells but does not reprogram their CTLA-4(hi)Bim(hi) tolerogenic phenotype. Blocking CTLA-4 is able to increase the expansion of interferon gamma (IFN-gamma)-producing HBV-specific CD8 T cells in both the peripheral and intrahepatic compartments. The rescue of anti-HBV responses by either CTLA-4 or PD-L1 blockade is nonredundant. Conclusion: CTLA-4 is expressed by HBV-specific CD8 T cells with high levels of Bim and helps to drive this proapoptotic phenotype. CTLA-4 blockade could form one arm of a therapeutic approach to modulate the diverse patterns of coregulation of T-cell exhaustion in this heterogeneous disease. (HEPATOLOGY 2011;53:1494-1503)