Regulated by the MicroRNA miR-181a Enhanced Activation-Dependent Signaling T Cells Have + Human Neonatal Naive CD4-猫眼课题宝

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2013

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David B. Lewis;Amy C. Palin;V. Ramachandran;Swati Acharya

与年龄较大的儿童和成人相比，人类新生儿对某些病原体的 CD4 + T 细胞免疫能力降低和延迟，但这些免疫功能发育差异的机制仍知之甚少。我们研究了这样的假设：人类新生儿 CD4 + T 细胞免疫受损是由于 ab -TCR/CD3 复合物和 CD28 结合后幼稚 CD4 + T 细胞的信号传导减少所致。令人惊讶的是，与来自成人外周血的幼稚 CD4 + T 细胞相比，来自脐带血 (CB) 的新生儿幼稚 CD4 + T 细胞中 CD3 参与后的钙通量显着更高。在成人 CD4 + 最近的胸腺移出中也观察到钙通量增强。新生儿幼稚 CD4 + T 细胞也具有较高的激活诱导的 Erk 磷酸化。与成体细胞相比，microRNA miR-181a 可增强小鼠胸腺细胞中激活诱导的钙流，在 CB 幼稚 CD4 + T 细胞中的表达水平显着更高。成人幼稚 CD4 + T 细胞中 miR-181a 的过度表达增加了激活诱导的钙流，这意味着 CB 幼稚 CD4 + T 细胞中 miR-181a 水平的增加有助于其信号传导增强。相比之下，与成体细胞相比，CB 幼稚 CD4 + T 细胞中的 AP-1 依赖性转录（位于 Erk 下游且是 T 细胞完全激活所需）减少。因此，CB 初始 CD4 + T 细胞具有增强的激活依赖性钙通量，表明胸腺细胞样表型的保留。增强的钙信号传导和 Erk 磷酸化与下游 AP-1 依赖性转录脱钩，后者减少并可能导致人类胎儿和新生儿 CD4 + T 细胞免疫的限制。免疫学杂志，2013，190：000–000。

Compared with older children and adults, human neonates have reduced and delayed CD4 + T cell immunity to certain pathogens, but the mechanisms for these developmental differences in immune function remain poorly understood. We investigated the hypothesis that impaired human neonatal CD4 + T cell immunity was due to reduced signaling by naive CD4 + T cells following engagement of the ab -TCR/CD3 complex and CD28. Surprisingly, calcium ﬂux following engagement of CD3 was signiﬁcantly higher in neonatal naive CD4 + T cells from umbilical cord blood (CB) compared with naive CD4 + T cells from adult peripheral blood. Enhanced calcium ﬂux was also observed in adult CD4 + recent thymic emigrants. Neonatal naive CD4 + T cells also had higher activation-induced Erk phosphorylation. The microRNA miR-181a, which enhances activation-induced calcium ﬂux in murine thymocytes, was expressed at signiﬁcantly higher levels in CB naive CD4 + T cells compared with adult cells. Overexpression of miR-181a in adult naive CD4 + T cells increased activation-induced calcium ﬂux, implying that the increased miR-181a levels of CB naive CD4 + T cells contributed to their enhanced signaling. In contrast, AP-1–dependent transcription, which is downstream of Erk and required for full T cell activation, was decreased in CB naive CD4 + T cells compared with adult cells. Thus, CB naive CD4 + T cells have enhanced activation-dependent calcium ﬂux, indicative of the retention of a thymocyte-like phenotype. Enhanced calcium signaling and Erk phosphorylation are decoupled from downstream AP-1–dependent transcription, which is reduced and likely contributes to limitations of human fetal and neonatal CD4 + T cell immunity. The Journal of Immunology , 2013, 190: 000–000.

Regulated by the MicroRNA miR-181a Enhanced Activation-Dependent Signaling T Cells Have + Human Neonatal Naive CD4

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