Targeting 2B4 Coinhibitory Signals During Sepsis-Induced Immune Dysregulation

导致免疫抑制的全身性免疫失调日益被认为是 导致败血症死亡的因素。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具有里程碑意义的研究表明，协同抑制 每个分子都在诱导T细胞耗竭方面扮演着不同的和非冗余的角色，这表明 在T细胞表面表达的不同的共抑制分子星座 免疫反应与T细胞功能和/或衰竭的不同阶段和程度有关。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 这可能会增加脓毒症期间的死亡风险。284(CD244，SLAMf4)是一种3SkD I型跨膜蛋白 一种蛋白质，是免疫球蛋白超家族中CD2亚群的成员，最为人所知的是它对NK的作用 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在脓毒症中的作用，我们在野生型盲肠结扎和穿刺术(CLP)中进行了诱导 284年，86只动物或那些基因缺陷的动物。令人惊讶的是，而野生动物表现出S2% 在CLP后，284只动物中只有13%死亡。因此，没有284只动物的情况是6次 败血症期间死亡的可能性较小。初步数据还表明，284在 脓毒症，并分析人类T细胞在急性脓毒症损伤期间的表达增加284 在CD4+和CDS+T细胞上，特别是记忆T细胞亚群上。因此，在这项提案中，我们的目标是 确定284是如何导致败血症引起的死亡的，它通过何种细胞类型(S)调节其影响，以及 在脓毒症期间，284会导致败血症引起的死亡。这项建议是创新的，因为我们的 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，标准的实验室小鼠只含有很小比例的记忆T细胞(2-5%)，这是因为 他们的SPF住房条件。因此，在这项资助中，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急性清除的病原体的小鼠 以产生“记忆小鼠”，即含有记忆T细胞的小鼠，其频率与 在成人中观察到(30%-50%)。我们将分析284在记忆中表达的CD4+和CDS+T细胞中的作用 细胞在脓毒症中诱导的免疫失调和死亡率，并确定284在诱导期间的影响 败血症对抗原特异性记忆T细胞对细菌和潜伏病毒“二次攻击”的反应。 抑制284介导的共抑制信号保护小鼠免受感染的机制 脓毒症期间的死亡对于未来针对这一点的免疫调节策略的潜在翻译至关重要。 预防败血症患者死亡的途径。 胡麻B.

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.