Protozoa Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
German Center for Infection Research Deutsches Zentrum für Infektionsforschung (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany.
Front Immunol. 2022 Jul 7;13:878320. doi: 10.3389/fimmu.2022.878320. eCollection 2022.
Activated cytotoxic CD8 T cells can selectively kill target cells in an antigen-specific manner. However, their prolonged activation often has detrimental effects on tissue homeostasis and function. Indeed, overwhelming cytotoxic activity of CD8 T cells can drive immunopathology, and therefore, the extent and duration of CD8 T cell effector function needs to be tightly regulated. One way to regulate CD8 T cell function is their suppression through engagement of co-inhibitory molecules to their cognate ligands (e.g., LAG-3, PD-1, TIM-3, TIGIT and CTLA-4). During chronic antigen exposure, the expression of co-inhibitory molecules is associated with a loss of T cell function, termed T cell exhaustion and blockade of co-inhibitory pathways often restores T cell function. We addressed the effect of co-inhibitory molecule expression on CD8 T cell function during acute antigen exposure using experimental malaria. To this end, we infected OT-I mice with a transgenic ANKA strain that expresses ovalbumin (PbTG), which enables the characterization of antigen-specific CD8 T cell responses. We then compared antigen-specific CD8 T cell populations expressing different levels of the co-inhibitory molecules. High expression of LAG-3 correlated with high expression of PD-1, TIGIT, TIM-3 and CTLA-4. Contrary to what has been described during chronic antigen exposure, antigen-specific CD8 T cells with the highest expression of LAG-3 appeared to be fully functional during acute malaria. We evaluated this by measuring IFN-γ, Granzyme B and Perforin production and confirmed the results by employing a newly developed T cell cytotoxicity assay. We found that LAG-3 CD8 T cells are more cytotoxic than LAG-3 or activated but LAG-3 CD8 T cells. In conclusion, our data imply that expression of co-inhibitory molecules in acute malaria is not necessarily associated with functional exhaustion but may be associated with an overwhelming T cell activation. Taken together, our findings shed new light on the induction of co-inhibitory molecules during acute T cell activation with ramifications for immunomodulatory therapies targeting these molecules in acute infectious diseases.
激活的细胞毒性 CD8 T 细胞可以以抗原特异性的方式选择性杀死靶细胞。然而，它们的长期激活通常对组织平衡和功能有不利影响。事实上，CD8 T 细胞的过度细胞毒性活性会导致免疫病理学，因此，CD8 T 细胞效应功能的程度和持续时间需要严格调节。调节 CD8 T 细胞功能的一种方法是通过其与同源配体（例如 LAG-3、PD-1、TIM-3、TIGIT 和 CTLA-4）的共抑制分子的结合来抑制它们。在慢性抗原暴露期间，共抑制分子的表达与 T 细胞功能的丧失相关，称为 T 细胞耗竭，阻断共抑制途径通常会恢复 T 细胞功能。我们在实验性疟疾中使用了一种方法来研究共抑制分子表达对急性抗原暴露期间 CD8 T 细胞功能的影响。为此，我们用表达卵清蛋白（PbTG）的转基因 ANKA 株感染 OT-I 小鼠，这使我们能够对抗原特异性 CD8 T 细胞反应进行特征分析。然后，我们比较了表达不同水平共抑制分子的抗原特异性 CD8 T 细胞群体。LAG-3 的高表达与 PD-1、TIGIT、TIM-3 和 CTLA-4 的高表达相关。与在慢性抗原暴露期间所描述的情况相反，在急性疟疾期间，LAG-3 表达最高的抗原特异性 CD8 T 细胞似乎具有完全功能。我们通过测量 IFN-γ、Granzyme B 和穿孔素的产生来评估这一点，并通过采用新开发的 T 细胞细胞毒性测定法确认了结果。我们发现，LAG-3 CD8 T 细胞比 LAG-3 或激活但 LAG-3 CD8 T 细胞更具细胞毒性。总之，我们的数据表明，急性疟疾中共抑制分子的表达不一定与功能耗竭相关，而可能与过度的 T 细胞激活相关。总之，我们的研究结果为急性感染性疾病中针对这些分子的免疫调节治疗提供了新的思路，并为急性 T 细胞激活期间共抑制分子的诱导提供了新的认识。
