Effects of HLA-antigen presentation machinery on the antiviral effectiveness of T lymphocytes.

HLA 抗原呈递机制对 T 淋巴细胞抗病毒效果的影响。

基本信息

批准号：
17590419
负责人：
UENO Takamasa
金额：
$ 2.3万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590419/
关键词：
Antigen T lymphocyte T cell receptor HIV AID S antiviral activity MHCクラスI 細胞傷害性T細胞抗原提示抗体ファージディスプレイ

项目摘要

A less effective HIV-specific cytotoxic T lymphocyte (CTL) response during a chronic HIV infection is an important factor for progressive immunopathogenesis, but how such CTLs are generated and accumulated remains elusive. Herein, we characterized CTL responses toward Pol, Env, and Nef optimal epitopes presented by HLA-B^*35, a human leukocyte antigen (HLA) associated with rapid disease progression. We found CTL escape variants within Pol and Nef epitopes that affected recognition by T cell receptors, although there was no mutation within the Env epitope. Analysis of peptide-HLA tetrameric complexes revealed that CD8 T cells exclusively specific for the Nef variant were generated following domination by the variant viruses. The variant-specific cells were capable of secreting antiviral cytokines but showed impaired antigen-specific proliferative responses ex vivo, whereas wild-type-specific ones had potent activities. Moreover, clonotypic CD8 T cells specific for the Pol variant showed diminished proliferation, whereas Env-specific ones had no functional he terogeneity. Taken together, our data indicate that antigenic variations that lead to a loss of T cell receptor recognition result not solely in the escape from established CTL responses, but also in decoy antigens that recruit less effective HlV-specific CTLs. Such a decoy antigen could have in part an actively negative effect on antiviral immune responses during a chronic HIV infection, providing us insights into the progressive immunopathogenesis as well as vaccine design against HIV infections.

慢性 HIV 感染期间，HIV 特异性细胞毒性 T 淋巴细胞 (CTL) 反应效果较差，是进行性免疫发病的重要因素，但此类 CTL 是如何产生和积累的仍然难以捉摸。在此，我们表征了针对 HLA-B^*35（一种与疾病快速进展相关的人类白细胞抗原 (HLA)）呈递的 Pol、Env 和 Nef 最佳表位的 CTL 反应。我们发现 Pol 和 Nef 表位内的 CTL 逃逸变体影响了 T 细胞受体的识别，尽管 Env 表位内没有突变。对肽-HLA四聚体复合物的分析表明，在变异病毒占主导地位后，产生了专门针对 Nef 变异的 CD8 T 细胞。变体特异性细胞能够分泌抗病毒细胞因子，但在体外表现出受损的抗原特异性增殖反应，而野生型特异性细胞则具有有效的活性。此外，Pol 变体特异性的克隆型 CD8 T 细胞显示增殖减少，而 Env 特异性的克隆型 CD8 T 细胞没有功能异质性。总而言之，我们的数据表明，导致 T 细胞受体识别丧失的抗原变异不仅会导致逃避已建立的 CTL 反应，还会导致诱饵抗原招募不太有效的 HIV 特异性 CTL。这种诱饵抗原可能在一定程度上对慢性艾滋病毒感染期间的抗病毒免疫反应产生积极的负面影响，使我们能够深入了解进行性免疫发病机制以及针对艾滋病毒感染的疫苗设计。