Neonatal CD8+ T cells resist terminal exhaustion during chronic infection [RNAseq_day8]

Chronic viral infections represent a major public health problem. Although it is well understood that neonates and adults respond differently to chronic viral infections (HIV, HCV), the underlying mechanisms remain poorly understood. In this study, we transferred neonatal and adult CD8+ T cells into a mouse model of chronic infection (LCMV clone 13) and dissected out the key cell-intrinsic differences that alter their ability to protect the host. Interestingly, we found that neonatal CD8+ T cells preferentially become effector cells early in chronic infection when compared to adult CD8+ T cells, and resist commitment to the exhausted differentiation trajectory. Further, neonatal CD8+ T cells are preferentially maintained as stem-like exhausted progenitors rather than terminally exhausted cells during the chronic phase of infection. The altered differentiation trajectories of neonatal and adult CD8+ T cells is functionally significant, for the neonatal cells protect from viral replication at the cost of early-onset immunopathology. Together, our work demonstrates how cell-intrinsic differences between neonatal and adult CD8+ T cells influences key cell fate decisions during chronic infection. Overall design: Adult (8-12 weeks old) or neonatal (5-7 days old) P14 transgenic CD8+ T cells were magnetically enriched, then adoptively transferred to congenically-distinct wildtype recipient mice (4,000 of each cell type). 1 day after adoptive transfer, recipient mice were infected with 2e6 PFU LCMV clone 13 systemically. 8 days post-infection, adult or neonatal donor cells were FACS sorted to at least 95% purity and subjected to RNA sequencing.

慢性病毒感染是一类重大公共卫生问题。尽管已知新生儿与成人对慢性病毒感染（人类免疫缺陷病毒HIV、丙型肝炎病毒HCV）的应答存在显著差异，但其背后的核心分子机制仍不甚明确。本研究将新生儿与成人的CD8+ T细胞（CD8+ T cell）移植至慢性感染小鼠模型（淋巴细胞脉络丛脑膜炎病毒克隆13，LCMV clone 13）中，解析了改变其宿主保护能力的关键细胞内在差异。有趣的是，相较于成人CD8+ T细胞，新生儿CD8+ T细胞在慢性感染早期更倾向于分化为效应细胞，并抵抗向耗竭分化轨迹的细胞定型。此外，在感染慢性期，新生儿CD8+ T细胞更倾向于维持为干细胞样耗竭前体细胞，而非终末耗竭细胞。新生儿与成人CD8+ T细胞分化轨迹的改变具有重要功能意义：新生儿细胞可抑制病毒复制，但需付出早发性免疫病理损伤的代价。综上，本研究阐明了新生儿与成人CD8+ T细胞之间的细胞内在差异，如何调控慢性感染过程中的关键细胞命运决定。整体实验设计：将成年（8~12周龄）或新生（5~7日龄）P14转基因CD8+ T细胞经磁珠富集后，以同源异型标记不同的野生型受体小鼠为宿主进行过继转移，每组细胞接种量为4000个。过继转移后1天，受体小鼠经全身途径接种2×10⁶噬斑形成单位（PFU）的LCMV克隆13。感染后8天，通过荧光激活细胞分选（FACS）将供体来源的成人或新生儿CD8+ T细胞分选至纯度不低于95%，随后进行RNA测序（RNA sequencing）。