Polyfunctional T Cells Accumulate in Large Human Cytomegalovirus-Specific T Cell Responses
Polyfunctional T Cells Accumulate in Large Human Cytomegalovirus-Specific T Cell Responses
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DOI：
10.1128/jvi.00873-11
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发表时间：
2012-01-01
影响因子：
5.4
通讯作者：
Kern, Florian
中科院分区：
文献类型：
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作者：
Lachmann, Raskit;Bajwa, Martha;Kern, Florian
在年轻人和老年人中都观察到了巨细胞病毒(CMV)特异性的CD8 T细胞反应。频繁的CMV重新激活被认为会耗尽这些细胞，使它们功能失调，因此需要更多的细胞来控制CMV。也可以看到CMV特异性的CD4T细胞的扩张，但研究较少。在这项研究中，我们用多色流式细胞术检测了不同年龄范围(20到84岁)的健康CMV感染者的T细胞对CMV pp65和IE-1主要抗原的反应。用CD40配体(CD40L)、白介素2(IL-2)、肿瘤坏死因子α(TNF-α)、干扰素(IFN-γ)和记忆标记CD27和CD45RA鉴定CMV特异性T细胞。在大反应中，效应记忆T细胞的比例增加，多功能CD8(干扰素-伽马(+)IL-2(+/-)肿瘤坏死因子-α(+))和CD4(CD40L(+/-)干扰素-伽马(+)IL-2(+)肿瘤坏死因子-α(+))T细胞亚群的比例增加，而幼稚T细胞的比例下降。CD4或CD8T细胞对pp65的反应越大，具有高级记忆表型的T细胞在整个(包括非CMV特异性)T细胞室中的比例就越大。此外，每个细胞的激活标记物的数量与T细胞受体下调的程度相关，这表明多功能细胞对抗原的敏感性增加。综上所述，我们的发现表明，即使在非常大的应答中，多功能的CMV特异性T细胞也不会被功能失调的细胞所取代。然而，与此同时，整个T细胞隔间的记忆亚群组成与T细胞对CMV pp65的反应的大小相关，证实了CMV感染对一些但不是所有感染者的免疫系统的强烈影响。
Large cytomegalovirus (CMV)-specific CD8 T-cell responses are observed in both young and, somewhat more often, old people. Frequent CMV reactivation is thought to exhaust these cells and render them dysfunctional so that larger numbers of them are needed to control CMV. Expansions of CMV-specific CD4 T cells are also seen but are less well studied. In this study, we examined the T-cell response to the dominant CMV pp65 and IE-1 antigens in healthy CMV-infected people across a wide age range (20 to 84 years) by using multicolor flow cytometry. CMV-specific T cells were characterized by the activation markers CD40 ligand (CD40L), interleukin-2 (IL-2), tumor necrosis factor alpha (TNF-alpha), and gamma interferon (IFN-gamma) and the memory markers CD27 and CD45RA. The proportions of effector memory T cells increased in large responses, as did the proportions of polyfunctional CD8 (IFN-gamma(+) IL-2(+/-) TNF-alpha(+)) and CD4 (CD40L(+/-) IFN-gamma(+) IL-2(+) TNF-alpha(+)) T-cell subsets, while the proportion of naive T cells decreased. The bigger the CD4 or CD8 T-cell response to pp65, the larger was the proportion of T cells with an advanced memory phenotype in the entire (including non-CMV-specific) T-cell compartment. In addition, the number of activation markers per cell correlated with the degree of T-cell receptor downregulation, suggesting increased antigen sensitivity in polyfunctional cells. In summary, our findings show that polyfunctional CMV-specific T cells were not superseded by dysfunctional cells, even in very large responses. At the same time, however, the memory subset composition of the entire T-cell compartment correlated with the size of the T-cell response to CMV pp65, confirming a strong effect of CMV infection on the immune systems of some, but not all, infected people.