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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，不太有效的HIV特异性细胞毒性T淋巴细胞（CTL）应答是进行性免疫发病机制的重要因素，但是这样的CTL如何产生和积累仍然是难以捉摸的。在此，我们表征了针对由HLA-B^*35（一种与快速疾病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应答。我们在Pol和Nef表位内发现了CTL逃逸变体，这些变体影响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揭示，在由变体病毒支配后产生了对Nef变体唯一特异性的CD 8 T细胞。变异特异性细胞能够分泌抗病毒细胞因子，但表现出受损的抗原特异性增殖反应离体，而野生型特异性的有强大的活动。此外，对Pol变体特异性的克隆型CD 8 T细胞显示增殖减少，而Env特异性的克隆型CD 8 T细胞没有功能性异质性。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从已建立的CTL应答中逃逸，而且还导致招募不太有效的HIV特异性CTL的诱饵抗原。这样的诱饵抗原可能在慢性HIV感染期间对抗病毒免疫应答具有部分积极的负面影响，为我们提供了对渐进性免疫发病机制以及针对HIV感染的疫苗设计的见解。