Department of Critical Care Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
Department of Critical Care Medicine, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China.
Front Immunol. 2024 Jul 22;15:1396157. doi: 10.3389/fimmu.2024.1396157. eCollection 2024.
The aim of this study was to clarify the relationship between expression level of CTLA-4 on CD4 T cells and sepsis-associated immunosuppression (SAI), and to elucidate the possible mechanism of mTOR pathway mediated autophagic-lysosomal disorder in regulating CTLA-4 expression.
We enrolled 63 sepsis patients admitted to our ICU between January 1 and June 30, 2023. Peripheral blood mononuclear cells were isolated from the patients within 24 hours of recruitment. Expression levels of mTOR, P62, LC3II, and CTLA-4 on circulating CD4 T lymphocytes were quantitated using flow cytometry. The association of these markers and relationship between CTLA-4 expression and the incidence of SAI and 28-day mortality were comprehensively analyzed.
Compared with non-immunosuppressed patients with sepsis, patients with SAI had a higher 28-day mortality rate (37.5% vs 13.0%, P=0.039) and higher CTLA-4 mean fluorescence intensity (MFI) on CD4 T cells (328.7 versus 78.7, P<0.0001). CTLA-4 MFI on CD4 cells was independently associated with the occurrence of SAI (95% confidence interval: 1.00-1.14, P=0.044). In patients with sepsis and SAI, non-survivors had higher CTLA-4 expression than survivors (sepsis: 427.5 versus 130.6, P=0.002; and SAI: 506.7 versus 225.2, P<0.0001). The sensitivity and specificity of CTLA-4 MFI at predicting 28-day mortality in patients with SAI was 100% and 80% respectively with the cutoff value of 328.7 and the area under the curve of 0.949. The MFI of mTOR, P62, and LC3II on CD4 T cells were statistically higher in patients with SAI than in non-immunosuppressed patients (267.2 versus 115.9, P<0.0001; 314.8 versus 173.7, P<0.0001; and 184.7 versus 1123.5, P=0.012, respectively); P62 and LC3II were markedly higher in non-survivors than in survivors of sepsis (302.9 versus 208.9, P=0.039; and 244.3 versus 122.8, P<0.0001 respectively). The expression of CTLA-4 statistically correlated with that of LC3II in patients with sepsis, patients with SAI, and patients with SAI who did not survive (correlation coefficient: 0.69, 0.68, and 0.73, respectively, P<0.0001).
CTLA-4 overexpression on CD4 T cells was markedly associated with the incidence of SAI and had great relevance to 28-day mortality. mTOR pathway mediated autophagic-lysosomal disorder showed significant association with CTLA-4 expression.
本研究旨在阐明 CTLA-4 在 CD4 T 细胞上的表达水平与脓毒症相关免疫抑制（SAI）之间的关系，并阐明 mTOR 通路介导的自噬溶酶体紊乱在调节 CTLA-4 表达中的可能机制。
我们纳入了 2023 年 1 月 1 日至 6 月 30 日期间入住我们 ICU 的 63 例脓毒症患者。在招募后 24 小时内从患者中分离外周血单核细胞。使用流式细胞术定量检测循环 CD4 T 淋巴细胞上的 mTOR、P62、LC3II 和 CTLA-4 的表达水平。综合分析这些标志物与 CTLA-4 表达之间的关联以及与 SAI 发生率和 28 天死亡率的关系。
与非免疫抑制性脓毒症患者相比，SAI 患者的 28 天死亡率更高（37.5% vs 13.0%，P=0.039），CD4 T 细胞上的 CTLA-4 平均荧光强度（MFI）也更高（328.7 与 78.7，P<0.0001）。CD4 细胞上的 CTLA-4 MFI 与 SAI 的发生独立相关（95%置信区间：1.00-1.14，P=0.044）。在脓毒症和 SAI 患者中，非幸存者的 CTLA-4 表达高于幸存者（脓毒症：427.5 与 130.6，P=0.002；SAI：506.7 与 225.2，P<0.0001）。SAI 患者中 CTLA-4 MFI 预测 28 天死亡率的灵敏度和特异性分别为 100%和 80%，截断值为 328.7，曲线下面积为 0.949。SAI 患者的 CD4 T 细胞上的 mTOR、P62 和 LC3II MFI 明显高于非免疫抑制性患者（267.2 与 115.9，P<0.0001；314.8 与 173.7，P<0.0001；和 184.7 与 1123.5，P=0.012）；在脓毒症患者中，非幸存者的 P62 和 LC3II 明显高于幸存者（302.9 与 208.9，P=0.039；和 244.3 与 122.8，P<0.0001）。CTLA-4 的表达与脓毒症患者、SAI 患者和未存活的 SAI 患者的 LC3II 表达呈统计学相关（相关系数：0.69、0.68 和 0.73，均 P<0.0001）。
CD4 T 细胞上 CTLA-4 的过度表达与 SAI 的发生明显相关，并与 28 天死亡率密切相关。mTOR 通路介导的自噬溶酶体紊乱与 CTLA-4 表达显著相关。
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