HCV epitope, homologous to multiple human protein sequences, induces a regulatory T cell response in infected patients
HCV epitope, homologous to multiple human protein sequences, induces a regulatory T cell response in infected patients
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DOI：
10.1016/j.jhep.2014.08.026
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发表时间：
2015-01-01
影响因子：
25.7
通讯作者：
Gregory, Stephen H.
中科院分区：
文献类型：
--
作者：
Losikoff, Phyllis T.;Mishra, Sasmita;Gregory, Stephen H.
背景与目的：丙型肝炎病毒感染的自发消退依赖于广泛的T细胞对多种病毒表位的反应。然而，大多数患者未能自发清除感染并发展为慢性病。丙型肝炎病毒感染者CD3(+)、CD4(+)、CD25(+)、FoxP3(+)调节性T细胞(T-(Reg))数量和功能的升高提示Treg细胞在病毒清除障碍中起作用。慢性丙型肝炎患者T-reg细胞活性升高的原因尚不清楚。方法：使用免疫信息学工具预测混杂的、高度保守的、由多个T细胞表位组成的人类白细胞抗原-DRB1限制性免疫原性共识序列(ICS)。这些序列被合成并添加到外周血单个核细胞(PBMC)的培养中，PBMC来自自发解决丙型肝炎病毒感染的患者、持续感染的患者和未感染的人。结果：免疫原性一致序列(ICS)可诱导感染者PBMC培养的Treg细胞显著增加，而自发清除丙型肝炎病毒的患者和非感染者的Treg细胞无明显变化。另一方面，一种类似的人类多肽(P7_794)在来自丙型肝炎病毒感染者和非感染者的PBMC中诱导了Treg细胞的显著增加。Janus Matrix分析表明，丙型肝炎病毒_G1_p7_794由Treg细胞表位组成，与人类蛋白质组表现出广泛的交叉反应。结论：具有广泛人类同源性的病毒编码肽(HCV_G1_P7_794)可激活CD3+CD4+CD25+FoxP3+天然Treg细胞，这可能与免疫抑制和慢性丙型肝炎的发展有关。(C)2014由Elsevier B.V.代表欧洲肝脏研究协会发表。
Background & Aims: Spontaneous resolution of hepatitis C virus (HCV) infection depends upon a broad T cell response to multiple viral epitopes. However, most patients fail to clear infections spontaneously and develop chronic disease. The elevated number and function of CD3(+)CD4(+)CD25(+)FoxP3(+) regulatory T cells (T-(reg)) in HCV-infected patients suggest a role of Treg cells in impaired viral clearance. The factors contributing to increased T-reg cell activity in chronic hepatitis C cases remain to be delineated.Methods: Immunoinformatics tools were used to predict promiscuous, highly-conserved HLA-DRB1-restricted immunogenic consensus sequences (ICS), each composed of multiple T cell epitopes. These sequences were synthesized and added to cultures of peripheral blood mononuclear cells (PBMCs), derived from patients who resolved HCV infection spontaneously, patients with persistent infection, and non-infected individuals. The cells were collected and following 5 days incubation, quantified and characterized by flow cytometry.Results: One immunogenic consensus sequence (ICS), HCV_G1_p7_794, induced a marked increase in Treg cells in PBMC cultures derived from infected patients, but not in patients who spontaneously cleared HCV or in non-infected individuals. An analogous human peptide (p7_794), on the other hand, induced a significant increase in Treg cells among PBMCs derived from both HCV-infected and non-infected individuals. Janus Matrix analyses determined that HCV_G1_p7_794 is comprised of Treg cell epitopes that exhibit extensive cross-reactivity with the human proteome.Conclusions: A virus-encoded peptide (HCV_G1_p7_794) with extensive human homology activates cross-reactive CD3+CD4+CD25+FoxP3+ natural Treg cells, which potentially contributes to immunosuppression and to the development of chronic hepatitis C. (C) 2014 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver.