C-Cbl expression levels regulate the functional responses of human central and effector memory CD4 T cells
C-Cbl expression levels regulate the functional responses of human central and effector memory CD4 T cells
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DOI：
10.1182/blood-2008-01-134486
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发表时间：
2008-08-01
期刊：
影响因子：
20.3
通讯作者：
Doucey, Marie-Agnes
中科院分区：
文献类型：
--
作者：
Brembilla, Nicolo C.;Weber, Johann;Doucey, Marie-Agnes
控制通过T细胞受体（TCR）触发的人类中央记忆（CM）和效应记忆（EM）T细胞应答的多种功能结果的生化机制仍然知之甚少。我们实施了反相蛋白阵列来分析离体分离的人CD 8和CD 4记忆T细胞亚群中的TCR信号传导组分。与CD 4 CM细胞相比，EM细胞表达统计学显著增加的SLP-76量和降低的c-Cbl、Syk、Fyn和LAT水平。此外，在EM细胞中，负调节因子c-Cbl的表达减少与c-Cbl激酶（Syk和Fyn）、PI 3 K和LAT的表达相关。重要的是，与c-Cbl表达降低一致，EM细胞显示出比CM细胞更低的功能阈值。增加EM细胞的c-Cbl含量到与使用胞质转导的CM细胞相同的水平，我们损害了它们的增殖和细胞因子的产生。这种调节机制主要取决于c-Cbl E3泛素连接酶活性，如通过酶缺陷的c-Cbl C381 A突变体对EM细胞功能的较弱影响所证明的。我们的研究报告c-Cbl作为记忆T细胞亚群的功能反应的关键调节剂，并首次在人类中确定了控制记忆CD 4细胞功能异质性的机制。
The biochemical mechanisms controlling the diverse functional outcomes of human central memory (CM) and effector memory (EM) T-cell responses triggered through the T-cell receptor (TCR) remain poorly understood. We implemented reverse phase protein arrays to profile TCR signaling components in human CD8 and CD4 memory T-cell subsets isolated ex vivo. As compared with CD4 CM cells, EM cells express statistically significant increased amounts of SLP-76 and reduced levels of c-Cbl, Syk, Fyn, and LAT. Moreover, in EM cells reduced expression of negative regulator c-Cbl correlates with expression of c-Cbl kinases (Syk and Fyn), PI3K, and LAT. Importantly, consistent with reduced expression of c-Cbl, EM cells display a lower functional threshold than CM cells. Increasing c-Cbl content of EM cells to the same level as that of CM cells using cytosolic transduction, we impaired their proliferation and cytokine production. This regulatory mechanism depends primarily on c-C,bl E3 ubiquitin ligase activity as evidenced by the weaker impact of enzymatically deficient c-Cbl C381 A mutant on EM cell functions. Our study reports c-Cbl as a critical regulator of the functional responses of memory T cell subsets and identifies for the first time in humans a mechanism controlling the functional heterogeneity of memory CD4 cells.