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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感染过程中，HIV特异性细胞毒性T淋巴细胞(CTL)反应效率较低，这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不清楚。在此，我们研究了针对人类白细胞抗原(HLAB^*35)提出的POL、Env和Nef最佳表位的CTL反应。我们在POL和Nef表位中发现了影响T细胞受体识别的CTL逃逸变异体，尽管在Env表位中没有突变。对多肽-HLA四聚体复合体的分析表明，Nef变异体病毒控制后产生了对Nef变异体特异的CD8T细胞。变异型特异性细胞能够分泌抗病毒细胞因子，但在体外表现出抗原特异性增殖反应受损，而野生型特异性细胞具有强大的活性。此外，Pol变异型的克隆型CD8T细胞的增殖能力减弱，而Env特异性的CD8T细胞没有功能异质性。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效率较低的HLV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，为我们提供了对进展的免疫发病机制以及针对HIV感染的疫苗设计的见解。