Comparison of human memory CD8 T cell responses to adenoviral early and late proteins in peripheral blood and lymphoid tissue.
Comparison of human memory CD8 T cell responses to adenoviral early and late proteins in peripheral blood and lymphoid tissue.
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DOI：
10.1371/journal.pone.0020068
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Flomenberg P
中科院分区：
文献类型：
--
作者：
Joshi A;Zhao B;Romanowski C;Rosen D;Flomenberg P
用衣壳蛋白六邻体特异性供体T细胞治疗造血干细胞移植(SCT)受者侵袭性腺病毒(Ad)病的研究正在进行中。我们认为，针对晚期蛋白Hexon的细胞毒性T细胞(CTL)在体内可能是无效的，因为早期的Ad蛋白E3-19K下调了感染细胞中的HLAI类抗原。本研究比较了针对早期调节蛋白DNA聚合酶(P-977)和晚期蛋白六邻体(H-892)高度保守的HLAA2限制性表位的CD8+T细胞在自然感染成人外周血(PB)和扁桃体中的作用。在扁桃体中，表位特异性五聚体检测到P-977+CD8+T细胞的频率显著高于H-892+CD8+T细胞；在外周血中这一趋势相反。扁桃体表位特异性T细胞表达干扰素-γ和IL-2，但不表达穿孔素或肿瘤坏死因子-α，而外周血T细胞则表达干扰素-γ、肿瘤坏死因子-α和穿孔素。扁桃体表位特异性T细胞表达淋巴归巢标志CCR7，活化标志CD25水平低于外周血T细胞，但增殖能力高于外周血T细胞。最后，与mRNA表达的动力学同步，P-977特异性CTL最早在感染后8小时就能裂解靶细胞。相反，H-892特异性CTL只有在感染的成纤维细胞被干扰素-γ处理以上调HLAI类抗原的情况下才能产生杀伤作用，并且细胞毒作用被推迟到16-24小时。这些数据表明，与Hexon CTL相比，中央记忆型DNA聚合CTL主宰淋巴间隔，在感染后更早地杀死成纤维细胞，而不需要外源性干扰素-γ。因此，使用针对早期和晚期Ad蛋白的CTL可以提高SCT受者对危及生命的Ad病的免疫治疗效果。
Treatment of invasive adenovirus (Ad) disease in hematopoietic stem cell transplant (SCT) recipients with capsid protein hexon-specific donor T cells is under investigation. We propose that cytotoxic T cells (CTLs) targeted to the late protein hexon may be inefficient in vivo because the early Ad protein E3-19K downregulates HLA class I antigens in infected cells. In this study, CD8+ T cells targeted to highly conserved HLA A2-restricted epitopes from the early regulatory protein DNA polymerase (P-977) and late protein hexon (H-892) were compared in peripheral blood (PB) and tonsils of naturally infected adults. In tonsils, epitope-specific pentamers detected a significantly higher frequency of P-977+CD8+ T cells compared to H-892+CD8+ T cells; this trend was reversed in PB. Tonsil epitope-specific CD8+ T cells expressed IFN-γ and IL-2 but not perforin or TNF-α, whereas PB T cells were positive for IFN-γ, TNF-α, and perforin. Tonsil epitope-specific T cells expressed lymphoid homing marker CCR7 and exhibited lower levels of the activation marker CD25 but higher proliferative potential than PB T cells. Finally, in parallel with the kinetics of mRNA expression, P-977-specific CTLs lysed targets as early as 8 hrs post infection. In contrast, H-892-specific CTLs did not kill unless infected fibroblasts were pretreated with IFN-γ to up regulate HLA class I antigens, and cytotoxicity was delayed until 16–24 hours. These data show that, in contrast to hexon CTLs, central memory type DNA polymerase CTLs dominate the lymphoid compartment and kill fibroblasts earlier after infection without requiring exogenous IFN-γ. Thus, use of CTLs targeted to both early and late Ad proteins may improve the efficacy of immunotherapy for life-threatening Ad disease in SCT recipients.
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DOI：
10.1073/pnas.0503726102
发表时间：
2005-07-05
影响因子：
11.1
作者：
Klebanoff, CA;Gattinoni, L;Restifo, NP
通讯作者：
Restifo, NP
影响因子：
15.3
作者：
Kim, Taeg S.;Hufford, Matthew M.;Braciale, Thomas J.
通讯作者：
Braciale, Thomas J.
影响因子：
5.4
作者：
BHAT, BM;WOLD, WSM
通讯作者：
WOLD, WSM
影响因子：
11.8
作者：
La Rosa, AM;Champlin, RE;Whimbey, E
通讯作者：
Whimbey, E
DOI：
10.1084/jem.20050227
发表时间：
2005-09-05
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Jelley-Gibbs DM;Brown DM;Dibble JP;Haynes L;Eaton SM;Swain SL
通讯作者：
Swain SL