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.

系统性免疫失调导致免疫抑制作用越来越被认为是主要的 败血症引起的死亡率的贡献者。但是，这种免疫抑制的基础机制是 不完全理解。在慢性病毒感染模型中的具有里程碑意义的研究表明，共抑制性 分子在诱导T细胞耗尽时扮演着不同和非冗余的角色，表明 在执行时在T细胞表面表达的不同共抑制分子的星座 免疫反应与T细胞功能和/或精疲力尽的不同阶段和程度相关。因此，我们 试图确定其他新型的共抑制分子是否参与免疫抑制期 这可能会增加败血症期间死亡率的风险。 284（CD244，SLAMF4）是3SKD I型跨膜 蛋白质和免疫球蛋白超家族的CD2子集的成员，以其在NK上的作用而闻名 细胞，但最近已被视为CD4+和CDS+ T细胞子集的共抑制受体。 为了确定败血症284的作用，我们在野生型中诱导了Cecal结扎和穿刺（CLP） 86只动物或遗传上缺乏284的动物。令人惊讶的是，野生型动物表现出S2％ CLP之后的死亡率，只有284个_，_动物死亡。因此，没有284种动物6次 败血症期间死亡的可能性较小。初步数据还表明，284个修改了免疫失调 败血症和对急性化脓性损伤期间人类T细胞的分析表明，284的表达增加 在CD4+和CDS+ T细胞上，尤其是在内存T细胞子集上。因此，在此提案中，我们的目标是 确定284种有助于败血症诱导的死亡率，介导其作用的细胞类型，并 当败血症期间284促进败血症引起的死亡率时。该提议具有创新性，因为我们 初步数据表明，在记忆CD4+和CDS+ T细胞上，284在人类和小鼠中高度表达。 但是，由于由于 他们的SPF住房条件。因此，在这笔赠款中，我们还提出了一种新的研究脓毒症的方法 发病机理：利用先前被几种急性清除病原体感染的小鼠 为了生成“记忆小鼠”；也就是说，包含内存T单元的小鼠以类似于该频率的频率 在成年人（30-50％）中观察到。我们将剖析284在内存CD4+和CD+ T中的作用 败血症引起的免疫失调和死亡率中的细胞，并确定在 抗原特异性记忆T细胞对细菌和潜在病毒“第二击”的败血症。 对抑制284个介导的共抑制信号的机制的询问可保护小鼠免受 败血症期间的死亡对于免疫调节策略的未来转换至关重要 防止化粪池患者死亡的途径。 B