アクティブボード・２００８年　9月
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研究発表を行った学会；
・第９回熊本エイズセミナー.
　平成２０年９月１８日～１９日(熊本)

タイトル；The decay of peptide-MHC complex influences antiviral activity of HIV-specific CTLs.
　
発表者；　本園　千尋　氏
　　　（熊本大学　エイズ学研究センター　ウイルス制御分野）
Abstract；
It is well known that a significant difference exists in the antiviral activities among HIV-specific CTLs. However, how CTL ’s specificity governs their antiviral activity is yet unclear. We addressed this issue based on immunodominant CTLs specific for 2 overlapping Nef epitopes, VY8 (VPLRPMTY) and RY11 (RPQVPLRPMTY). Firstly, VY8-specific CTLs showed more potent antiviral activity toward HIV-infected primary CD4+ cells than RY11-specific ones. To delineate how VY8-specific CTLs had more potent antiviral activity, we sought to reconstruct several VY8- and RY11-specific TCRs on TCR-deficient T cells. T-cell sensitizing assays showed that VY8-specific TCRs had higher sensitivity to peptide-loaded target cells than RY11-specific ones. However, HLA-tetramer binding assays did not support such difference in their TCR-ligand interactions. Employing a novel assay to track the decay of the peptide-MHC complex (pMHC) using TCR-reconstructed cells, we found that the VY8/HLA-B35 complex were more stable on the target cell surface than the RY11/HLA-B35 complex. Moreover, using a series of various variant peptides, we found that both of VY8-5A (VPLRAMTY) and RY11-8A (RPQVPLRAMTY) in complex with HLA-B35 were substantially stabilized compared to their wild-type peptides. Because the alanine substitution at Pro-82 of NefSF2 resulted in the generation of both VY8-5A and RY11-8A, we asked whether pMHC stability influences the susceptibility to killing Nef-expressing target cells by CTLs. Both CTLs more profoundly killed the cells expressing the Ala-82 Nef, suggesting that the pMHC decay was associated with increased susceptibility to killing by CTLs. Taken together, our results highlight the significant effects of intrinsic pMHC stability on the efficient CTL killing of HIV-infected cells, providing us with an additional insight into vaccine design．