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种主要的免疫抑制机制。 脓毒症导致的死亡率。然而，这种免疫抑制的机制是 不完全理解。在慢性病毒感染模型中进行的里程碑式研究表明， 每个分子在诱导T细胞耗竭中发挥不同的和非冗余的作用，这表明 在执行一个免疫抑制过程中，T细胞表面上表达的不同共抑制分子的星座， 免疫应答与T细胞功能和/或耗竭不同阶段和程度相关。因此我们 试图确定是否有其他新的共抑制分子参与免疫抑制阶段 这可能会增加败血症期间的死亡风险。284（CD 244，SLAMf 4）是3SkD I型跨膜 免疫球蛋白超家族CD 2亚群的一种蛋白质和成员，以其在NK细胞上的作用而闻名 细胞，但最近被认为是CD 4+和CDS+ T细胞亚群上的共抑制受体。 为了确定284在脓毒症中的作用，我们诱导了野生型小鼠盲肠结扎穿孔（CLP）。 86只动物或284只动物中有遗传缺陷的动物。引人注目的是，野生型动物表现出S2% CLP后，284只动物中只有13%死亡。因此，284只动物缺席6次 死于败血症的可能性更小初步数据还表明，284可以改变免疫失调， 脓毒症，并且在急性脓毒症损伤期间对人T细胞的分析揭示了284 对CD 4+和CD 8 + 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如何促成脓毒症诱导的死亡率，其介导其作用的细胞类型，以及 当在脓毒症期间284导致脓毒症诱导的死亡时。这项建议的创新之处在于， 初步数据显示284在人和小鼠中在记忆性CD 4+和CDS+ T细胞上高度表达。 然而，标准实验室小鼠仅含有非常小百分比的记忆T细胞（2-5%），这是由于 SPF住房条件。因此，在这项资助中，我们还提出了一种新的方法来研究脓毒症 发病机制：利用先前感染了几种急性清除的病原体的小鼠， 为了产生“记忆小鼠”;也就是说，小鼠含有记忆T细胞的频率与 在成年人中观察到（30-50%）。我们将分析284在记忆性CD 4+和CD 5 + T细胞上表达的作用， 细胞在脓毒症诱导的免疫失调和死亡率，并确定284诱导的影响， 脓毒症对抗原特异性记忆T细胞对细菌和潜伏病毒“第二次攻击”的反应。 对284介导的共抑制信号的抑制保护小鼠免于 脓毒症期间的死亡对于未来潜在的免疫调节策略的翻译至关重要， 预防脓毒症患者死亡的途径。 B。