Transcriptome of IL-18R-alpha hi and lo mouse CD8+ T cells during acute response to high dose influenza A infection

High expression of interleukin-18 receptor alpha on T cells defines pro-inflammatory rather than cytotoxic effector functions and underlies severe respiratory diseaseHyperactivated immune responses underpin severe disease outcomes in respiratory viral infections, yet specific immune perturbations in life-threatening diseases are ill-defined. Our recent findings identified oleoyl-ACP-hydrolase (OLAH), host enzyme mediating fatty acid production, as a driver of severe viral diseases. Here, in the same patient cohorts, we identified the gene encoding IL-18R-alpha chain, as being highly expressed in life-threatening influenza, COVID-19, RSV and MIS-C; strongly correlating with OLAH. Using a mouse model of severe influenza disease, we showed that high IL-18R-alpha expression on effector T-cells was associated with disease severity and defined pro-inflammatory rather than cytotoxic effector functions. Our analyses of endogenous CD8+ T-cells and adoptively-transferred OT-I cells during influenza virus infection revealed phenotypic, functional and transcriptomic features of IL-18R-alpha hi and IL-18R-alpha lo T-cells. IL-18R-alpha hi T-cells were pro-inflammatory and polyfunctional, with high expression of cytokine and chemokine inflammatory transcripts, and genes linked to the NFkappaB pathway. Conversely, IL-18R-alpha lo T-cells had high expression of cytotoxicity-related transcripts, including granzymes and perforin, together with high KLRG-1 levels. Our study showed, for the first time, how expression of IL-18R-alpha impacts severe and fatal respiratory disease outcome, and how IL-18R-alpha defines functionally distinct T-cell populations: pro-inflammatory IL-18R-alpha hi and cytotoxic IL-18R-alpha lo subsets.

T细胞表面高表达白细胞介素18受体α链（interleukin-18 receptor alpha, IL-18Rα）可定义促炎而非细胞毒性的效应功能，并为重症呼吸道疾病的发病机制提供依据。呼吸道病毒感染引发的过度激活免疫应答是导致重症疾病结局的核心原因，但危及生命的重症呼吸道感染中存在的特异性免疫紊乱仍尚不明确。我们前期研究发现，介导脂肪酸生成的宿主酶油酰-ACP水解酶（oleoyl-ACP-hydrolase, OLAH）是重症病毒性疾病的致病驱动因子。本研究针对同一患者队列展开分析，发现编码IL-18Rα链的基因在危及生命的流感、新型冠状病毒肺炎（COVID-19）、呼吸道合胞病毒（RSV）感染以及儿童多系统炎症综合征（MIS-C）患者体内均呈高表达，且其表达水平与OLAH的表达显著相关。借助重症流感小鼠模型，我们证实效应T细胞表面高表达IL-18Rα与疾病严重程度密切相关，并可定义促炎而非细胞毒性的效应功能。通过对流感病毒感染过程中的内源性CD8+ T细胞以及过继转移的OT-I细胞进行分析，我们揭示了IL-18Rα高表达（IL-18Rα hi）与IL-18Rα低表达（IL-18Rα lo）T细胞的表型、功能及转录组特征：IL-18Rα hi T细胞呈现促炎表型且具备多功能性，高表达细胞因子与趋化因子类炎性转录本，以及与核因子κB（NF-κB）通路相关的基因；与之相反，IL-18Rα lo T细胞则高表达颗粒酶、穿孔素等细胞毒性相关转录本，同时伴随高表达杀伤细胞凝集素样受体G1（KLRG-1）。本研究首次阐明了IL-18Rα的表达如何影响重症及致死性呼吸道疾病的转归，并明确了IL-18Rα可定义功能迥异的两类T细胞亚群：促炎型IL-18Rα hi T细胞与细胞毒性型IL-18Rα lo T细胞。