Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, Iowa, United States of America.
Department of Pathology, University of Iowa, Iowa City, Iowa, United States of America.
PLoS Pathog. 2023 Oct 12;19(10):e1011720. doi: 10.1371/journal.ppat.1011720. eCollection 2023 Oct.
Sepsis, an amplified immune response to systemic infection, is characterized by a transient cytokine storm followed by chronic immune dysfunction. Consequently, sepsis survivors are highly susceptible to newly introduced infections, suggesting sepsis can influence the function and composition of the naïve CD8 T cell pool and resulting pathogen-induced primary CD8 T cell responses. Here, we explored the extent to which sepsis induces phenotypic and functional changes within the naïve CD8 T cell pool. To interrogate this, the cecal ligation and puncture (CLP) mouse model of polymicrobial sepsis was used. In normal, non-septic mice, we show type-I interferon (IFN I)-mediated signaling plays an important role in driving the phenotypic and functional heterogeneity in the naïve CD8 T cell compartment leading to increased representation of Ly6C+ naïve CD8 T cells. In response to viral infection after sepsis resolution, naïve Ly6C+ CD8 T cells generated more primary effector and memory CD8 T cells with slower conversion to a central memory CD8 T cell phenotype (Tcm) than Ly6C- naïve CD8 T cells. Importantly, as a potent inducer of cytokine storm and IFN I production, sepsis leads to increased representation of Ly6C+ naïve CD8 T cells that maintained their heightened ability to respond (i.e., effector and memory CD8 T cell accumulation and cytokine production) to primary LCMV infection. Lastly, longitudinal analyses of peripheral blood samples obtained from septic patients revealed profound changes in CD8 T cell subset composition and frequency compared to healthy controls. Thus, sepsis has the capacity to alter the composition of naïve CD8 T cells, directly influencing primary CD8 T cell responses to newly introduced infections.
脓毒症是一种全身性感染引起的过度免疫反应，其特征是短暂的细胞因子风暴，随后出现慢性免疫功能障碍。因此，脓毒症幸存者极易受到新引入的感染，这表明脓毒症可以影响初始 CD8 T 细胞库的功能和组成，以及由此产生的病原体诱导的初始 CD8 T 细胞反应。在这里，我们探讨了脓毒症在初始 CD8 T 细胞库中引起表型和功能变化的程度。为了探究这一点，我们使用了盲肠结扎和穿孔（CLP）的多微生物脓毒症小鼠模型。在正常非脓毒症小鼠中，我们表明 I 型干扰素（IFN I）介导的信号在驱动初始 CD8 T 细胞库中的表型和功能异质性中起着重要作用，导致 Ly6C+初始 CD8 T 细胞的代表性增加。在脓毒症解决后对病毒感染的反应中，与 Ly6C-初始 CD8 T 细胞相比，Ly6C+初始 CD8 T 细胞产生了更多的原始效应和记忆 CD8 T 细胞，转化为中央记忆 CD8 T 细胞表型（Tcm）的速度较慢。重要的是，脓毒症作为细胞因子风暴和 IFN I 产生的有效诱导剂，导致 Ly6C+初始 CD8 T 细胞的代表性增加，这些细胞保持了对原发性 LCMV 感染的高度反应能力（即效应和记忆 CD8 T 细胞的积累和细胞因子的产生）。最后，对脓毒症患者外周血样本的纵向分析与健康对照相比，发现 CD8 T 细胞亚群组成和频率发生了深刻变化。因此，脓毒症有能力改变初始 CD8 T 细胞的组成，直接影响初始 CD8 T 细胞对新引入的感染的反应。
