Early emergence of T central memory precursors programs clonal dominance during chronic viral infection [bulkRNAseq]

Chronic infection with cytomegalovirus (CMV) leads to long-term maintenance of extraordinarily large CMV-specific T cell populations. The magnitude of this so-called ‘memory inflation’ is thought to be mainly determined by the availability of antigenic stimuli during the chronic phase of infection. However, by mapping the long-term development of CD8+ T cell families derived from single naive precursors, we find that T cell fate decisions, taken during the acute phase of murine CMV infection, can alter the level of memory inflation by more than 1000-fold. Counterintuitively, a T cell family’s capacity for memory inflation is not determined by its initial clonal expansion. Instead, those rare T cell families that strongly dominate the chronic phase of infection show an early transcriptomic signature akin to that of established T central memory cells. Accordingly, a T cell family’s long-term dominance is best predicted by its early content of T central memory precursors, which later serve as a stem cell-like source for the antigen-driven maintenance of memory inflation. Of sixteen single cell derived OT-1 T cell families 100 progeny cells were sorted from spleen at day 8 post infection with MCMV-ie2-SIINFEKL. BulkRNA-Seq was performed for each of the populations.

巨细胞病毒（cytomegalovirus, CMV）慢性感染可长期维持规模极其庞大的CMV特异性T细胞群体。这种被称为“记忆通胀”的细胞库扩增现象，既往认为主要由感染慢性阶段的抗原刺激可及性所决定。然而，通过对单一初始前体CD8阳性T细胞（CD8+ T cell）谱系的长期发育过程进行图谱绘制，我们发现小鼠巨细胞病毒（murine CMV, MCMV）感染急性期做出的T细胞命运决定，可使记忆通胀水平产生超过1000倍的差异。
与直觉相悖的是，T细胞谱系的记忆通胀能力并非由其初始克隆扩增规模所决定。相反，那些在感染慢性阶段占据绝对主导地位的罕见T细胞谱系，其早期转录组特征与已确立的中枢记忆T细胞（T central memory cells）相似。据此，预测T细胞谱系长期主导地位的最佳指标，是其早期中枢记忆前体细胞的占比——这类前体细胞后续可作为干细胞样细胞源，通过抗原驱动维持记忆通胀的持续发展。
本数据集包含16个单细胞起源的OT-1 T细胞（OT-1 T cell）谱系：在感染MCMV-ie2-SIINFEKL后的第8天，从脾脏中分选得到100个子代细胞群体，对每个群体均开展了批量RNA测序（Bulk RNA-Seq）。