Laboratory of Translational Immunology, Humanitas Clinical and Research Center - IRCCS, Rozzano, Milan, Italy.
Innovative Immunotherapies Unit, Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Nat Immunol. 2020 Dec;21(12):1552-1562. doi: 10.1038/s41590-020-0791-5. Epub 2020 Oct 12.
T cell memory relies on the generation of antigen-specific progenitors with stem-like properties. However, the identity of these progenitors has remained unclear, precluding a full understanding of the differentiation trajectories that underpin the heterogeneity of antigen-experienced T cells. We used a systematic approach guided by single-cell RNA-sequencing data to map the organizational structure of the human CD8 memory T cell pool under physiological conditions. We identified two previously unrecognized subsets of clonally, epigenetically, functionally, phenotypically and transcriptionally distinct stem-like CD8 memory T cells. Progenitors lacking the inhibitory receptors programmed death-1 (PD-1) and T cell immunoreceptor with Ig and ITIM domains (TIGIT) were committed to a functional lineage, whereas progenitors expressing PD-1 and TIGIT were committed to a dysfunctional, exhausted-like lineage. Collectively, these data reveal the existence of parallel differentiation programs in the human CD8 memory T cell pool, with potentially broad implications for the development of immunotherapies and vaccines.
T 细胞记忆依赖于产生具有干细胞样特性的抗原特异性祖细胞。然而，这些祖细胞的身份仍不清楚，这妨碍了对基础抗原经验 T 细胞异质性的分化轨迹的全面理解。我们使用单细胞 RNA 测序数据指导的系统方法，描绘了生理条件下人类 CD8 记忆 T 细胞库的组织结构。我们鉴定了两个以前未被识别的、克隆性、表观遗传上、功能上、表型上和转录上不同的干细胞样 CD8 记忆 T 细胞亚群。缺乏抑制性受体程序性死亡蛋白 1（PD-1）和 T 细胞免疫受体含有 Ig 和 ITIM 结构域（TIGIT）的祖细胞被定向到一个功能性谱系，而表达 PD-1 和 TIGIT 的祖细胞则被定向到一个功能失调的、耗竭样谱系。总的来说，这些数据揭示了人类 CD8 记忆 T 细胞库中存在平行的分化程序，这可能对免疫疗法和疫苗的发展具有广泛的意义。
