CD4 T cell dysfunction and reprogramming during sepsis

脓毒症仍然是全球死亡的主要原因（2017年报告了1100万例脓毒症相关死亡）， 并且与治疗脓毒症患者相关的费用给医疗保健行业带来了巨大的负担。败血症 是由宿主对感染的反应失调引起的危及生命的器官功能障碍。初期 脓毒症的特征是由促炎细胞因子驱动的过度炎症（即，IL-1β、IL-6、IFNγ和TNF）。 在脓毒症急性期存活的患者显示出免疫功能的长期损害。的这种状态 慢性免疫麻痹使脓毒症幸存者越来越容易继发感染。 因此，迫切需要更好地了解急性脓毒症的细胞和分子基础 病理生理学和随后的免疫重编程，其定义了延长的免疫抑制。 CD 4 T细胞，对于协调针对一系列病原体的细胞和体液免疫应答至关重要 在正常情况下，在脓毒症的急性阶段严重耗尽。的总数 随着时间的推移，CD 4 T细胞逐渐恢复，但其功能能力在数月内仍然钝化。为 在过去的10年里，我们一直专注于我们的研究，以追求了解脓毒症是如何发生的长期目标。 影响CD 4 T细胞区室，因为CD 4 T细胞在细胞的整体适应性中起着关键作用。 免疫系统我们将继续研究CD 4 T细胞的细胞和分子重编程 未来研究的三个相互关联的领域：1）定义调控机制， CD 4 T（Treg）细胞在脓毒症期间扩增; 2）使用基因组学进行综合发现方法， 蛋白质组学和代谢组学来阐明脓毒症病理生理学和CD 4 T细胞的分子基础。 免疫麻痹;以及3）确定脓毒症期间肠道微生物群功能障碍如何影响 的细胞因子风暴，促进CD 4 T细胞免疫麻痹和迟发性 mortality.我们将询问从多个脓毒症患者队列中获得的样本，以及来自 在Ag特异性CD 4 T细胞群水平上的脓毒症临床前小鼠模型。我们的临床前研究 将通过使用一种新的小鼠模型来进一步加强，该模型模拟了人类生物学的一个关键方面- 接触多种正在进行和已解决的感染会训练免疫系统对新感染产生强有力的反应 病原体-并将作为一个重要的和新的'过渡翻译'临床前桥梁之间 人类和SPF实验室小鼠，以机械地研究CD 4 T细胞功能障碍和重编程， 败血症解决这些关于脓毒症对CD 4 T细胞生物学影响的关键知识缺口， 揭示了新的干预点，可以在未来开发，以恢复CD 4 T细胞介导的免疫力， 和整体免疫适应性的影响。

Sepsis remains a major cause of death worldwide (11 million sepsis-related deaths were reported in 2017), and that costs associated with treating septic patients place a large burden on the healthcare industry. Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Early stages of sepsis are marked by hyperinflammation driven by proinflammatory cytokines (i.e., IL-1β, IL-6, IFNγ, and TNF). Patients who survive the acute phase of sepsis display long-term impairments in immune function. This state of chronic immunoparalysis renders sepsis survivors increasingly susceptible to secondary infections. Consequently, there is a desperate need to better understand the cellular and molecular basis of acute sepsis pathophysiology and subsequent immune reprogramming that defines the prolonged immune suppression. CD4 T cells, essential for coordinating the cellular and humoral immune response to a range of pathogens under normal circumstances, are severely depleted during the acute stage of sepsis. The overall number of CD4 T cells gradually recover over time, but their functional capacity remains blunted for many months. For the past 10 years, we have focused our research to pursue the long-term goal of understanding how sepsis impacts the CD4 T cell compartment because of the key role played by CD4 T cells in the overall fitness of the immune system. We will continue our investigation of the cellular and molecular reprogramming of CD4 T cells during sepsis in three interconnected areas of future research: 1) Define the mechanism(s) by which regulatory CD4 T (Treg) cells expand during sepsis; 2) Perform an integrated discovery approach using genomics, proteomics, and metabolomics to elucidate the molecular basis of sepsis pathophysiology and CD4 T cell immunoparalysis; and 3) Determine how intestinal microbiota dysfunction during sepsis affects the magnitude of the cytokine storm and promotes CD4 T cell immunoparalysis and increased incidence of late-onset mortality. We will interrogate samples obtained from multiple cohorts of sepsis patients, as well as from preclinical mouse models of sepsis at the level of Ag-specific CD4 T cell populations. Our preclinical studies will be further strengthened by using a novel mouse model that mimics a critical aspect of human biology – exposure to multiple ongoing and resolved infections trains the immune system for robust responses to new pathogens – and will serve as an important and novel ‘transitional translational’ preclinical bridge between humans and SPF laboratory mice to mechanistically study CD4 T cell dysfunction and reprogramming during sepsis. Addressing these key gaps in knowledge regarding the effect of sepsis on CD4 T cell biology will likely reveal new points of intervention that can be exploited in the future to restore CD4 T cell-mediated immunity, and overall immune fitness, following sepsis.