Targeting 2B4 Coinhibitory Signals During Sepsis-Induced Immune Dysregulation

在脓毒症引起的免疫失调期间靶向 2B4 共抑制信号

• 批准号: 8818803
• 负责人: Craig M Coopersmith
• 金额: $ 29.64万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8818803
• 关键词: Acute; Adult; Animals; Antibiotics; Antigens; CD8B1 gene; Cause of Death; Cell Survival; Cell physiology; Cells; Cessation of life; Chronic; Clinical; Comorbidity; Data; Etiology; Exhibits; Frequencies; Future; Genetic; Grant; Heart Diseases; Housing; Human; Immune; Immune response; Immunoglobulins; Immunosuppression; Immunosuppressive Agents; Infection; Injury; Integral Membrane Protein; Intervention; Investigation; Laboratory mice; Ligation; Lymphocyte; Malignant Neoplasms; Mediating; Memory; Modeling; Mus; Natural Killer Cells; Pathogenesis; Pathway interactions; Patients; Phase; Play; Public Health; Puncture procedure; Risk; Role; Sepsis; Signal Transduction; Staging; Supportive care; Surface; T cell response; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Therapeutic; Time; Translations; United States; Up-Regulation; Viral; Virus Diseases; apoptosis in lymphocytes; cell type; cytokine; exhaustion; innovation; member; mortality; mouse model; novel; novel strategies; pathogen; prevent; public health relevance; receptor; septic

Systemic immune dysregulation leading to immune suppression is increasingly being recognized as a major contributor to sepsis-induced mortality. However, the mechanisms underlying this immune suppression are incompletely understood. Landmark studies in models of chronic viral infection have revealed that coinhibitory molecules each play distinct and non-redundant roles in inducing T cell exhaustion, suggesting that the constellation of distinct coinhibitory molecules expressed on the surface of T cells during the execution of an immune response correlate to different stages and degrees of T cell function and/or exhaustion. Thus, we sought to determine whether other novel coinhibitory molecules participate in the immunosuppressive phase that may increase the risk of mortality during sepsis. 284 (CD244, SLAMf4) is a 3SkD type I transmembrane protein and member of the CD2 subset of the immunoglobulin superfamily that is best known for its role on NK cells but has more recently been appreciated as a coinhibitory receptor on subsets of CD4+ and CDS+ T cells. In order to determine the role of 284 during sepsis, we induced cecal ligation and puncture (CLP) in wild-type 86 animals or those that were genetically deficient in 284. Strikingly, while wild-type animals exhibited S2% mortality following CLP, only 13% of 284_,_ animals died. Thus, the absence of 284 rendered animals 6 times less likely to die during sepsis. Preliminary data also suggests that 284 modifies immune dysregulation during sepsis, and analysis of human T cells during acute septic injury revealed an increase in the expression of 284 on both CD4+ and CDS+ T cells, in particular on memory T cell subsets. Thus, in this proposal we aim to determine how 284 contributes to sepsis-induced mortality, the cell type(s) by which it mediates its effects, and when during sepsis 284 contributes to sepsis-induced mortality. This proposal is innovative in that our preliminary data reveal that 284 is highly expressed in humans and mice on memory CD4+and CDS+ T cells. However, standard laboratory mice contain only a very small percentage of memory T cells (2-5%), owing to their SPF housing conditions. Thus, in this grant, we also propose a novel approach to study sepsis pathogenesis: to utilize mice that have been previously infected with several acutely cleared pathogens in order to generate "memory mice"; that is, mice that contain memory T cells at a frequency similar to that observed in adult humans (30-50%). We will dissect the role of 284 expressed on memory CD4+ and CDS+ T cells in sepsis-induced immune dysregulation and mortality, and determine the impact of 284 induced during sepsis on antigen-specific memory T cell responses to both a bacterial and a latent viral "second hit". Interrogation of the mechanisms by which inhibition of 284-mediated coinhibitory signals protects mice from death during sepsis is critical for the potential future translation of immunomodulatory strategies to target this pathway to prevent death in septic patients. B.

导致免疫抑制的系统性免疫失调越来越被认为是一个主要的疾病。 脓毒症引起的死亡的一个重要因素。然而，这种免疫抑制的机制是 不完全理解。慢性病毒感染模型的里程碑式研究表明，共抑制 每个分子在诱导 T 细胞耗竭方面发挥着独特且非冗余的作用，这表明 在执行某项任务期间，T 细胞表面表达的一系列不同的共抑制分子 免疫反应与 T 细胞功能和/或耗竭的不同阶段和程度相关。因此，我们 试图确定其他新型共抑制分子是否参与免疫抑制阶段 这可能会增加败血症期间的死亡风险。 284（CD244，SLAMf4）是3SkD I型跨膜 蛋白质，是免疫球蛋白超家族 CD2 子集的成员，以其对 NK 的作用而闻名 细胞，但最近被认为是 CD4+ 和 CDS+ T 细胞亚群的共抑制受体。 为了确定284在败血症期间的作用，我们在野生型中诱导盲肠结扎和穿刺（CLP） 86 只动物或 284 只存在遗传缺陷的动物。引人注目的是，野生型动物表现出 S2% CLP 后的死亡率，284_,_ 动物中只有 13% 死亡。因此，缺少 284 只动物 6 次 败血症期间死亡的可能性较小。第284章 284 第284章 CD4+ 和 CDS+ T 细胞，特别是记忆 T 细胞亚群。因此，在本提案中，我们的目标是 确定284如何导致脓毒症引起的死亡率、它介导其影响的细胞类型，以及 败血症期间 284 会导致败血症引起的死亡。这个提议的创新之处在于我们 初步数据显示，284 在人类和小鼠的记忆 CD4+ 和 CDS+ T 细胞上高度表达。 然而，标准实验室小鼠仅含有很小比例的记忆 T 细胞 (2-5%)，这是由于 他们的 SPF 住房条件。因此，在这笔资助中，我们还提出了一种研究脓毒症的新方法 发病机制：利用先前感染过几种经过急性清除的病原体的小鼠 为了产生“记忆老鼠”；也就是说，含有频率与此类似的记忆 T 细胞的小鼠 在成年人中观察到（30-50%）。我们将剖析284在记忆CD4+和CDS+ T上表达的作用 第284章 败血症对抗原特异性记忆 T 细胞对细菌和潜伏病毒“第二次打击”的反应产生影响。 探究抑制 284 介导的共抑制信号可保护小鼠免受 败血症期间的死亡对于未来免疫调节策略的潜在转化至关重要 预防脓毒症患者死亡的途径。 B.