Infants suffer disproportionately from respiratory infections and generate reduced vaccine responses compared with adults, although the underlying mechanisms remain unclear. In adult mice, lung-localized, tissue-resident memory T cells (TRMs) mediate optimal protection to respiratory pathogens, and we hypothesized that reduced protection in infancy could be due to impaired establishment of lung TRM. Using an infant mouse model, we demonstrate generation of lung-homing, virus-specific T effectors after influenza infection or live-attenuated vaccination, similar to adults. However, infection during infancy generated markedly fewer lung TRMs, and heterosubtypic protection was reduced compared with adults. Impaired TRM establishment was infant–T cell intrinsic, and infant effectors displayed distinct transcriptional profiles enriched for T-bet–regulated genes. Notably, mouse and human infant T cells exhibited increased T-bet expression after activation, and reduction of T-bet levels in infant mice enhanced lung TRM establishment. Our findings reveal that infant T cells are intrinsically programmed for short-term responses, and targeting key regulators could promote long-term, tissue-targeted protection at this critical life stage.

尽管其基本机制尚不清楚，但婴儿比成年人遭受呼吸道感染的比例要高得多，并且产生的疫苗反应也会减少。在成年小鼠中，肺部定位的组织驻留记忆T细胞（TRM）介导了对呼吸道病原体的最佳保护作用，我们假设婴儿期保护作用降低可能是由于肺TRM的建立受损所致。使用婴儿小鼠模型，我们证明了在流感感染或减毒活疫苗接种后，与成年人相似，肺归巢，病毒特异性T效应子的产生。但是，婴儿期感染明显减少了肺TRMs，与成人相比，异型保护作用降低了。TRM的建立受到婴儿T细胞固有功能的影响，婴儿效应子显示出独特的转录谱，富含T-bet调控的基因。值得注意的是，小鼠和人类婴儿T细胞在激活后表现出增加的T-bet表达，而婴儿小鼠中T-bet水平的降低则增强了肺TRM的建立。我们的发现表明，婴儿T细胞在本质上是为短期反应而编程的，在这一关键生命阶段，靶向关键调节剂可以促进长期，针对组织的保护。