T Cells of Infants Are Mature, but Hyporeactive Due to Limited Ca²⁺ Influx

CD4 T cells in human infants and adults differ in the initiation and strength of their responses. The molecular basis for these differences is not yet understood. To address this the principle key molecular events of TCR- and CD28-induced signaling in naive CD4 T cells, such as Ca2+ influx, NFAT expression, phosphorylation and translocation into the nucleus, ERK activation and IL-2 response, were analyzed over at least the first 3 years of life. We report dramatically reduced IL-2 and TNFα responses in naive CD31+ T cells during infancy. Looking at the obligatory Ca2+ influx required to induce T cell activation and proliferation, we demonstrate characteristic patterns of impairment for each stage of infancy that are partly due to the differential usage of Ca2+ stores. Consistent with those findings, translocation of NFATc2 is limited, but still dependent on Ca2+ influx as demonstrated by sensitivity to cyclosporin A (CsA) treatment. Thus weak Ca2+ influx functions as a catalyst for the implementation of restricted IL-2 response in T cells during infancy. Our studies also define limited mobilization of Ca2+ ions as a characteristic property of T cells during infancy. This work adds to our understanding of infants’ poor T cell responsiveness against pathogens.人类婴儿与成人的CD4 T细胞在免疫应答的启动过程与应答强度上均存在差异，此类差异的分子机制目前仍未阐明。为阐明该机制，本研究针对出生后至少前3年内的初始型CD4 T细胞（naive CD4 T cells）中T细胞受体（TCR）与CD28介导的信号通路核心分子事件展开分析，涵盖钙离子内流（Ca²⁺ influx）、活化T细胞核因子（NFAT）表达、磷酸化及核转位、细胞外调节蛋白激酶（ERK）激活以及白细胞介素-2（IL-2）应答等关键环节。研究发现，婴儿期初始型CD31+ T细胞的IL-2与肿瘤坏死因子-α（TNFα）应答水平显著降低。针对诱导T细胞激活与增殖所必需的钙离子内流，本研究揭示了婴儿期各阶段T细胞应答受损的特征性模式，该现象部分源于细胞内钙库使用方式的差异。与此一致的是，活化T细胞核因子c2（NFATc2）的核转位过程受到限制，但仍依赖于钙离子内流——这一点可通过环孢素A（CsA）处理后的敏感性实验得以证实。由此可见，钙离子内流不足是婴儿期T细胞IL-2应答受限的关键诱因。本研究同时明确，钙离子动员受限是婴儿期T细胞的特征性表型。本研究有助于进一步阐明婴儿T细胞对病原体应答能力低下的分子机制。