美国埃默里大学Rafi Ahmed研究小组发现适应急性或慢性病毒感染的早期前体CD8 T细胞。该研究于2025年1月8日在线发表于国际一流学术期刊《自然》。

研究人员探讨了在慢性病毒感染和癌症中对维持T细胞免疫至关重要的、具有干细胞特征的CD8+ T细胞的来源和分化，这些细胞还在PD-1导向的免疫治疗中发挥关键作用。这些PD-1+ TCF-1+ TOX+ 干细胞样CD8+ T细胞，也被称为耗竭T细胞的前体，具有独特的程序，使它们能够适应慢性抗原刺激。

通过使用慢性LCMV感染的小鼠模型，研究人员发现病毒特异性干细胞样CD8+ T细胞在慢性感染的早期（第5天）就被生成，表明这一关键的命运确立发生在感染结果无关的情况下。事实上，研究人员发现无论是在急性还是慢性LCMV感染的早期，几乎相同的干细胞样CD8+ T细胞群体都会被生成，并且抗原对于维持干细胞样表型至关重要。

接下来，研究人员进行互惠的过继性转移实验，以确定这些早期干细胞样CD8+ T细胞在病毒清除与持续感染后的命运。在将慢性感染小鼠的第5天干细胞样CD8+ T细胞，转移到急性感染小鼠体内后，这些细胞下调了慢性干细胞样CD8+ T细胞的经典标记，并表达与中枢记忆CD8+ T细胞相关的标记（CD127和CD62L）。相反，当将急性感染小鼠的第5天干细胞样细胞，转移到慢性感染小鼠中时，这些CD8+ T细胞像慢性资源细胞一样发挥作用，并有效地响应PD-1治疗。

这些发现突出了这些早期PD-1+ TCF-1+ TOX+ 干细胞样CD8+ T细胞，根据急性或慢性病毒感染适应其分化轨迹的能力。最重要的是，该研究表明，宿主在事先已做好准备，以应对潜在的慢性感染。

附：英文原文

Title: An early precursor CD8 T cell that adapts to acute or chronic viral infection

Author: McManus, Daniel T., Valanparambil, Rajesh M., Medina, Christopher B., Scharer, Christopher D., McGuire, Donald J., Sobierajska, Ewelina, Hu, Yinghong, Chang, Daniel Y., Wieland, Andreas, Lee, Judong, Nasti, Tahseen H., Hashimoto, Masao, Ross, James L., Prokhnevska, Nataliya, Cardenas, Maria A., Gill, Amanda L., Clark, Elisa C., Abadie, Kathleen, Kumar, Arjun, Kaye, Jonathan, Au-Yeung, Byron B., Kueh, Hao Yuan, Kissick, Haydn T., Ahmed, Rafi

Issue&Volume: 2025-01-08

Abstract: This study examines the origin and differentiation of stem-like CD8+ T cells that are essential for sustained T cell immunity in chronic viral infections and cancer and also play a key role in PD-1 directed immunotherapy1-10. These PD-1+ TCF-1+ TOX+ stem-like CD8+ T cells, also referred to as precursors of exhausted T cells8,9, have a distinct program that allows them to adapt to chronic antigen stimulation. Using the mouse model of chronic LCMV infection we found that virus specific stem-like CD8+ T cells are generated early (day 5) during chronic infection suggesting that this crucial fate commitment occurs irrespective of infection outcome. Indeed, we found that nearly identical populations of stem-like CD8+ T cells were generated early during acute or chronic LCMV infection, and that antigen was essential for maintaining the stem-like phenotype. We next performed reciprocal adoptive transfer experiments to determine the fate of these early stem-like CD8+ T cells after viral clearance versus persistence. Following transfer of day 5 stem-like CD8+ T cells from chronically infected into acutely infected mice, these cells downregulated canonical markers of the chronic stem-like CD8+ T cells and expressed markers (CD127 and CD62L) associated with central memory CD8+ T cells. Reciprocally, when day 5 stem-like cells from acutely infected mice were transferred into chronically infected mice these CD8+ T cells functioned like chronic resource cells and responded effectively to PD-1 therapy. These findings highlight the ability of these early PD-1+ TCF-1+ TOX+ stem-like CD8+ T cells to adapt their differentiation trajectory to either an acute or chronic viral infection. Most importantly, our study shows that the host is prepared a priori to deal with a potential chronic infection.

DOI: 10.1038/s41586-024-08562-y

Source: https://www.nature.com/articles/s41586-024-08562-y