病毒性出血热是具有共同临床特征的一组疾病。近期研究发现重症患者高死亡率与T淋巴细胞高表达共抑制分子密切相关。在多种病毒性出血热患者体内，我们发现表达四种共抑制分子的独特PD-1+TIGIT+TIM-3+LAG3+CD8+T细胞亚群（PTTL细胞）。既往研究认为高表达共抑制分子的T细胞表现为功能降低的“耗竭”状态。但我们发现：PTTL细胞高表达与细胞毒相关的重要分子穿孔素和颗粒酶B，其细胞数目和组织损伤的多项临床指标密切相关，由此提出“PTTL细胞并不是经典的耗竭T细胞，而是导致造成组织损伤的重要效应细胞。”申请人拟以PTTL为研究靶点，采用临床队列，鉴定其表型、功能、T细胞受体多样性及代谢特征；采用动物模型证实其免疫损伤作用；明确诱导PTTL细胞产生的因素及导致其炎性免疫功能增强的信号通路，阐明病毒性出血热这一类传染病重症发生的共同机制，为临床判断患者预后提供指标，为免疫治疗提供靶点。

Viral hemorrhagic fever is a group of diseases with common clinical features.Recent studies have found that high mortality in critically ill patients is closely related to high expression of co-inhibitory molecules in T-lymphocyte. In a variety of patients with viral hemorrhagic fever, we found a unique PD-1+TIGIT+TIM-3+LAG3+CD8+Tcell subset (PTTL cells) expressing four co-inhibitory molecules. Previous studies have suggested that T cells that express high co-inhibitory molecules appear to be "exhausted" states with reduced function. However, we found that PTTL cells highly expressed cytotoxic protein (perforin and granzyme B), and their proportions are closely related to many clinical indicators of tissue damage, suggesting that "PTTL cells are not classical exhausted T cells, but a group of important effector cells that cause tissue damage." Applicants intend to use PTTL cells as the research target, using viral hemorrhagic fever cohorts to identify their phenotypes, functions, T cell receptor repertoire diversity and metabolic characteristics; using dengue and yellow fever viral infection animal models to confirm their relevance with tissue damage; to Clarify the factors that cause PTTL cells induction and the regulated signal pathway leading to its inflammatory immune function, and elucidate the common mechanism of severe episodes of viral hemorrhagic fever. It's promising to provide several indicators for clinical prediction of prognosis, and provide novel targets for immunotherapy of viral hemorrhagic fever.