Ozga Aleksandra J, Moalli Federica, Abe Jun, Swoger Jim, Sharpe James, Zehn Dietmar, Kreutzfeldt Mario, Merkler Doron, Ripoll Jorge, Stein Jens V
Theodor Kocher Institute, University of Bern, 3012 Bern, Switzerland.
Systems Biology Research Unit, European Molecular Biology Laboratory/Centre for Genomic Regulation, Barcelona Institute of Science and Technology, 08003 Barcelona, Spain.
J Exp Med. 2016 Nov 14;213(12):2811-2829. doi: 10.1084/jem.20160206. Epub 2016 Oct 31.
During adaptive immune responses, CD8 T cells with low TCR affinities are released early into the circulation before high-affinity clones become dominant at later time points. How functional avidity maturation is orchestrated in lymphoid tissue and how low-affinity cells contribute to host protection remains unclear. In this study, we used intravital imaging of reactive lymph nodes (LNs) to show that T cells rapidly attached to dendritic cells irrespective of TCR affinity, whereas one day later, the duration of these stable interactions ceased progressively with lowering peptide major histocompatibility complex (pMHC) affinity. This correlated inversely BATF (basic leucine zipper transcription factor, ATF-like) and IRF4 (interferon-regulated factor 4) induction and timing of effector differentiation, as low affinity-primed T cells acquired cytotoxic activity earlier than high affinity-primed ones. After activation, low-affinity effector CD8 T cells accumulated at efferent lymphatic vessels for egress, whereas high affinity-stimulated CD8 T cells moved to interfollicular regions in a CXCR3-dependent manner for sustained pMHC stimulation and prolonged expansion. The early release of low-affinity effector T cells led to rapid target cell elimination outside reactive LNs. Our data provide a model for affinity-dependent spatiotemporal orchestration of CD8 T cell activation inside LNs leading to functional avidity maturation and uncover a role for low-affinity effector T cells during early microbial containment.
在适应性免疫反应过程中，低TCR亲和力的CD8 T细胞在高亲和力克隆在后期占主导地位之前就早早释放到循环系统中。淋巴细胞组织中功能性亲和力成熟是如何协调的，以及低亲和力细胞如何对宿主保护做出贡献仍不清楚。在本研究中，我们利用反应性淋巴结的活体成像显示，T细胞无论TCR亲和力如何都能迅速附着于树突状细胞，而一天后，随着肽主要组织相容性复合体（pMHC）亲和力降低，这些稳定相互作用的持续时间逐渐缩短。这与BATF（碱性亮氨酸拉链转录因子，ATF样）和IRF4（干扰素调节因子4）的诱导以及效应器分化的时间呈负相关，因为低亲和力启动的T细胞比高亲和力启动的T细胞更早获得细胞毒性活性。激活后，低亲和力效应性CD8 T细胞在输出淋巴管处聚集以便流出，而高亲和力刺激的CD8 T细胞以CXCR3依赖的方式迁移到滤泡间区域，以持续接受pMHC刺激并延长扩增。低亲和力效应性T细胞的早期释放导致反应性淋巴结外的靶细胞迅速被清除。我们的数据提供了一个模型，用于说明淋巴结内CD8 T细胞激活的亲和力依赖性时空协调，从而导致功能性亲和力成熟，并揭示了低亲和力效应性T细胞在早期微生物控制中的作用。
