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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.

在慢性HIV感染期间，HIV特异性细胞毒性T淋巴细胞（CTL）反应不太有效是进行性免疫发病的一个重要因素，但这种CTL是如何产生和积累的仍然是未知的。本文中，我们表征了CTL对Pol、Env和Nef最佳表位的反应，这些表位由HLA- b ^*35（一种与疾病快速进展相关的人白细胞抗原（HLA））呈递。我们发现Pol和Nef表位内的CTL逃逸变异会影响T细胞受体的识别，尽管Env表位内没有突变。肽- hla四聚体复合物的分析显示，在Nef变异病毒控制后，产生了特异性的CD8 T细胞。变异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具有强大的活性。此外，Pol变异特异性的克隆型CD8 T细胞增殖减弱，而env特异性的CD8 T细胞则没有功能异质性。综上所述，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导致逃避已建立的CTL反应，而且还导致诱骗抗原招募不太有效的hla特异性CTL。这种诱饵抗原可能在一定程度上对慢性HIV感染期间的抗病毒免疫反应产生积极的负面影响，为我们提供了对进行性免疫发病机制以及针对HIV感染的疫苗设计的见解。