Comparative analysis of transcriptional profiling of CD3+, CD4+ and CD8+ T cells identifies novel immune response players in T-cell activation.
Comparative analysis of transcriptional profiling of CD3+, CD4+ and CD8+ T cells identifies novel immune response players in T-cell activation.
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DOI：
10.1186/1471-2164-9-225
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发表时间：
2008-05-16
期刊：
影响因子：
4.4
通讯作者：
Papoutsakis, Eleftherios T
中科院分区：
文献类型：
--
作者：
Wang, Min;Windgassen, Dirk;Papoutsakis, Eleftherios T
t细胞活化是免疫反应的一个重要步骤，依赖于数百个基因/蛋白质的严格控制，但这一复杂过程背后的细胞和分子事件尚未完全了解，特别是在基因组规模上。值得注意的是，两种t细胞亚群（CD4+和CD8+）相互之间以及自然混合群体（CD3+细胞）之间的比较基因组规模转录分析仍未探索。CD3+ T细胞与CD4+和CD8+亚群之间基于微阵列的基因表达模式的比较揭示了在很大程度上保守但不相同的转录模式。我们采用了基因本体论驱动的转录分析与蛋白质丰度分析相结合，以鉴定与免疫反应相关的新的t细胞激活基因和细胞类型特异性基因。我们确定了参与两个亚群之间交流的潜在基因（包括IL23A、NR4A2、CD83、PSMB2、-8、MIF、IFI16、TNFAIP1、POU2AF1和OTUB1）和潜在的效应功能特异性基因（XCL2、SLAMF7、TNFSF4、-5、-9、CSF3、CD48和CD244）。在T细胞活化过程中诱导的趋化因子，包括CCL20、CXCL9、-10、-11（在所有三种人群中）和XCL2（优先在CD8+ T细胞中），但以前未在T细胞中发现。其他意想不到的细胞因子（GPI， OSM和MIF）的表达增加表明它们参与t细胞活化，其功能尚待研究。许多受体的差异表达，包括CCR5、CCR7、IL1R2、IL1RAP、IL6R、TNFRSF25和TNFRSF1A，以前未在t细胞激活的背景下报道，表明它们在这种免疫过程中的作用。参与TCR激活的几个受体(CD3D、CD3G、TRAT1、ITGAL、ITGB1、ITGB2、CD8A和B （CD8+ t细胞特异性）以及LCK、ZAP70和TYROBP同步下调。细胞表面受体（HLA-Ds和KLRs）的成员，之前没有在t细胞激活的背景下被发现，也被下调。这种对CD4+和CD8+亚群以及混合CD3+群体中t细胞激活的比较基因组规模转录分析使得鉴定许多以前未在t细胞激活背景下鉴定的免疫应答基因成为可能。值得注意的是，这使得鉴定许多先前已知的T细胞激活基因的时间模式成为可能，并且还鉴定了涉及CD4+和CD8+ T细胞的效应功能和通信的基因。
T-cell activation is an essential step of the immune response and relies on the tightly controlled orchestration of hundreds of genes/proteins, yet the cellular and molecular events underlying this complex process are not fully understood, especially at the genome-scale. Significantly, a comparative genome-scale transcriptional analysis of two T-cell subsets (CD4+ and CD8+) against each other and against the naturally mixed population (CD3+ cells) remains unexplored. Comparison of the microarray-based gene expression patterns between CD3+ T cells, and the CD4+ and CD8+ subsets revealed largely conserved, but not identical, transcriptional patterns. We employed a Gene-Ontology-driven transcriptional analysis coupled with protein abundance assays in order to identify novel T-cell activation genes and cell-type-specific genes associated with the immune response. We identified potential genes involved in the communication between the two subsets (including IL23A, NR4A2, CD83, PSMB2, -8, MIF, IFI16, TNFAIP1, POU2AF1, and OTUB1) and would-be effector-function-specific genes (XCL2, SLAMF7, TNFSF4, -5, -9, CSF3, CD48 and CD244). Chemokines induced during T-cell activation, but not previously identified in T cells, include CCL20, CXCL9, -10, -11 (in all three populations), and XCL2 (preferentially in CD8+ T cells). Increased expression of other unexpected cytokines (GPI, OSM and MIF) suggests their involvement in T-cell activation with their functions yet to be examined. Differential expression of many receptors, not previously reported in the context of T-cell activation, including CCR5, CCR7, IL1R2, IL1RAP, IL6R, TNFRSF25 and TNFRSF1A, suggests their role in this immune process. Several receptors involved in TCR activation (CD3D, CD3G, TRAT1, ITGAL, ITGB1, ITGB2, CD8A and B (CD8+ T-cell specific) along with LCK, ZAP70 and TYROBP were synchronously downregulated. Members of cell-surface receptors (HLA-Ds and KLRs), none previously identified in the context of T-cell activation, were also downregulated. This comparative genome-scale, transcriptional analysis of T-cell activation in the CD4+ and CD8+ subsets and the mixed CD3+ populations made possible the identification of many immune-response genes not previously identified in the context of T-cell activation. Significantly, it made possible to identify the temporal patterns of many previously known T-cell activation genes, and also identify genes implicated in effector functions of and communication between CD4+ and CD8+ T cells.