Epigenetic signature of PD-1+ TCF1+ CD8 T cells that act as resource cells during chronic viral infection and respond to PD-1 blockade.

We have recently defined a novel population of PD-1+ TCF1+ virus-specific CD8 T cells that function as resource cells during chronic LCMV infection and provide the proliferative burst seen after PD-1 blockade. Such CD8 T cells have been found in other chronic infections and also in cancer in mice and humans. These CD8 T cells exhibit stem-like properties undergoing self-renewal and also giving rise to the terminally differentiated (exhausted) CD8 T cells. Here we compared the epigenetic signature of stemlike CD8 T cells with exhausted CD8 T cells. ATAC-seq analysis showed that stem-like CD8 T cells had a unique signature implicating activity of TCF (HMG family) and NF-κB (RHD family) members. In addition, transcription factor networks including Tcf7, Id3, and Bach2 were enriched in stem-like CD8 T cells. In contrast, exhausted CD8 T cells enriched accessible sites for ETS and Runx motifs in addition to a network encompassing Prdm1 and Il10. We also compared the epigenetic signatures of the two CD8 T-cell subsets from chronically infected mice with effector and memory CD8 T cells generated after an acute LCMV infection. Both CD8 T-cell subsets generated during chronic infection were strikingly different from CD8 T-cell subsets from acute infection. Interestingly, the stem-like CD8 T-cell subset from chronic infection, despite sharing key functional properties with memory CD8 T cells, had a very distinct epigenetic program. These results show that the chronic stem-like CD8 T-cell program represents a specific adaptation of the T-cell response to persistent antigenic stimulation.

我们近期定义了一类新型的PD-1(Programmed Death 1)+ TCF1(T Cell Factor 1)+ 病毒特异性CD8阳性T细胞(CD8 T cells)亚群，该类细胞在慢性LCMV(Lymphocytic Choriomeningitis Virus)感染过程中充当储备细胞，并可在PD-1阻断治疗后引发特征性的增殖爆发。此类CD8阳性T细胞已在其他慢性感染以及小鼠与人类的肿瘤组织中被发现。这类CD8阳性T细胞具备干细胞样特性：可进行自我更新，同时可分化为终末耗竭(exhausted)的CD8阳性T细胞。本研究中，我们对比了干细胞样CD8阳性T细胞与耗竭性CD8阳性T细胞的表观遗传特征(epigenetic signature)。ATAC-seq(Assay for Transposase-Accessible Chromatin using sequencing)分析显示，干细胞样CD8阳性T细胞具有独特的表观遗传特征，提示TCF（HMG(High Mobility Group)家族）与NF-κB（RHD(Rel Homology Domain)家族）家族成员的活性。此外，干细胞样CD8阳性T细胞中富集了包含Tcf7、Id3及Bach2在内的转录因子调控网络。与之相反，耗竭性CD8阳性T细胞则富集了ETS与Runx基序的开放染色质位点，同时包含Prdm1与Il10的调控网络。我们还对比了慢性感染小鼠体内两种CD8阳性T细胞亚群，与急性LCMV感染后产生的效应性CD8阳性T细胞及记忆性CD8阳性T细胞的表观遗传特征。慢性感染过程中产生的两种CD8阳性T细胞亚群，与急性感染来源的CD8阳性T细胞亚群均存在显著差异。有趣的是，尽管慢性感染来源的干细胞样CD8阳性T细胞亚群与记忆性CD8阳性T细胞共享关键的功能特性，但其表观遗传程序却截然不同。上述结果表明，慢性感染环境下的干细胞样CD8阳性T细胞程序，是T细胞应答对持续性抗原刺激的一种特异性适应机制。