Institute of Medical Microbiology and Hygiene, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Department of Internal Medicine IV, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
PLoS Pathog. 2020 Sep 29;16(9):e1008870. doi: 10.1371/journal.ppat.1008870. eCollection 2020 Sep.
The two T-box transcription factors T-bet and Eomesodermin (Eomes) are important regulators of cytotoxic lymphocytes (CTLs), such as activated CD8 T cells, which are essential in the fight against intracellular pathogens and tumors. Both transcription factors share a great degree of homology based on sequence analysis and as a result exert partial functional redundancy during viral infection. However, the actual degree of redundancy between T-bet and Eomes remains a matter of debate and is further confounded by their distinct spatiotemporal expression pattern in activated CD8 T cells. To directly investigate the functional overlap of these transcription factors, we generated a new mouse model in which Eomes expression is under the transcriptional control of the endogenous Tbx21 (encoding for T-bet) locus. Applying this model, we demonstrate that the induction of Eomes in lieu of T-bet cannot rescue T-bet deficiency in CD8 T cells during acute lymphocytic choriomeningitis virus (LCMV) infection. We found that the expression of Eomes instead of T-bet was not sufficient for early cell expansion or effector cell differentiation. Finally, we show that imposed expression of Eomes after acute viral infection promotes some features of exhaustion but must act in concert with other factors during chronic viral infection to establish all hallmarks of exhaustion. In summary, our results clearly underline the importance of T-bet in guiding canonical CTL development during acute viral infections.
两个 T 盒转录因子 T 细胞特异性转录因子（T-bet）和 Eomesodermin（Eomes）是细胞毒性淋巴细胞（CTL），如激活的 CD8 T 细胞的重要调节因子，它们在对抗细胞内病原体和肿瘤方面至关重要。基于序列分析，这两种转录因子具有高度同源性，因此在病毒感染过程中发挥部分功能冗余。然而，T-bet 和 Eomes 之间的实际冗余程度仍然存在争议，并且由于它们在激活的 CD8 T 细胞中的独特时空表达模式而进一步复杂化。为了直接研究这些转录因子的功能重叠，我们生成了一种新的小鼠模型，其中 Eomes 的表达受内源性 Tbx21（编码 T-bet）基因座的转录控制。应用该模型，我们证明了 Eomes 的诱导替代 T-bet 不能在淋巴细胞性脉络丛脑膜炎病毒（LCMV）感染期间挽救 CD8 T 细胞中的 T-bet 缺陷。我们发现，Eomes 的表达而不是 T-bet 不足以进行早期细胞扩增或效应细胞分化。最后，我们表明，在急性病毒感染后强制表达 Eomes 可促进衰竭的一些特征，但在慢性病毒感染期间必须与其他因素协同作用才能建立衰竭的所有特征。总之，我们的结果清楚地强调了 T-bet 在指导急性病毒感染期间典型 CTL 发育中的重要性。
