Memory T Cell Cosigning Pathways in Sepsis-Induced Immune Dysregulation

摘要/概要 最近评估脓毒症患者免疫表型和功能的研究增加了我们对脓毒症的认识。 了解脓毒症期间发生的免疫失调。新的范式表明， T细胞共刺激和共抑制分子的平衡对于决定T细胞免疫应答的结果是至关重要的。 激活和/或失调。一种对T细胞最关键的共刺激分子 活化是CD 28。CD 28是一种有效的共刺激受体，在幼稚T细胞上是所需的次级信号 促进最佳的T细胞活化。已经显示在脓毒症期间CD 28在CD 4 + T细胞上下调。 以及小鼠和人类中的CD 8 + T细胞。这些表达数据导致了CD 28 下调可能有助于脓毒症后的免疫抑制。然而，CD 28的功能作用 脓毒症期间存在争议，因为其他研究表明CD 28阻断在几种情况下具有保护作用 败血症的鼠模型。值得注意的是，CD 28在幼稚T细胞与记忆T细胞上的表达存在差异。此外，委员会认为， 甚至保留CD 28表达的记忆T细胞也可能对CD 28信号传导的依赖性降低， activation.这一点很重要，因为记忆T细胞约占人类T细胞区室的50 大多数人成年时，但在实验室小鼠中的频率要低得多（<5%）。因此我们 我假设，脓毒症中CD 28的相互矛盾的报道和不清楚的作用可能是由于不同的 对记忆和幼稚T细胞的作用。为了检验这一假设，并更好地模拟抗原经历的 人类患者的免疫系统，在上一个资助周期中，我们开发了一种模型来产生小鼠， 拥有与成年人更相似的记忆T细胞区室， 败血症这项工作最近发表在JCI Insight上。简言之，将未处理动物依次感染 不同的急性清除细菌和病毒感染。这种方法产生了具有~20%的CD 4+的小鼠， ~60%的CD 8+记忆T细胞，但实际感染完全解决，没有病毒/细菌。 在约38天后可检测到，从而减轻持续感染的任何影响。然后对小鼠进行盲肠结扎 和穿刺（CLP）。令人信服的是，我们的初步数据揭示了CD 28阻断的惊人但相反的效果 对脓毒症诱导的死亡率的影响。当用以下药物治疗幼稚实验室动物时， 抗-CD 28导致死亡率增加，用抗-CD 28治疗经历抗原的“记忆小鼠”， 与未处理的记忆对照相比，CD 28导致死亡率显著降低。这里我们 我们建议询问抑制CD 28介导的共刺激信号的机制， “记忆小鼠”，但不是幼稚的实验室动物在败血症期间死亡。这些研究意义重大， 高度临床相关，因为它们将促进免疫调节策略的发展， CD 28通路对生理相关细胞类型的作用，以防止脓毒症患者死亡。

Abstract/ Summary Recent studies assessing the immune phenotypes and functionality of septic patients have increased our understanding of the immune dysregulation that occurs during sepsis. The new paradigm suggests that the balance of T cell costimulatory and coinhibitory molecules is critical to determining the outcome of T cell activation and/or dysregulation during sepsis. One costimulatory molecule that is most critical to T cell activation is CD28. CD28 is a potent costimulatory receptor and on naïve T cells is a required secondary signal that promotes optimal T cell activation. CD28 has been shown to be down-regulated during sepsis on CD4+ and CD8+ T cells in both mice and humans. These expression data have led to the supposition that CD28 down-regulation may contribute to immune suppression following sepsis. However, the functional role of CD28 during sepsis is controversial, as other studies have shown a protective effect of CD28 blockade in several murine models of sepsis. Of note, CD28 is differentially expressed on naïve vs. memory T cells. Moreover, even memory T cells which retain CD28 expression may have reduced dependence on CD28 signaling for activation. This is important because memory T cells constitute roughly 50% of the human T cell compartment by the time most people reach adulthood but are much less frequent (<5%) in laboratory mice. Thus, we hypothesized that the conflicting reports and unclear role of CD28 during sepsis may be due to a differential role on memory vs. naïve T cells. In order to test this hypothesis and better model the antigen-experienced immune system of human patients, during the last funding cycle we developed a model to generate mice that possess a memory T cell compartment more similar to that of adult humans, that could then be rendered septic. This work was recently published in JCI Insight. Briefly, naïve animals were sequentially infected with different acutely cleared bacterial and viral infections. This approach generates a mouse with ~20% CD4+ and ~60% CD8+ memory T cells, but the actual infections are completely resolved and no virus/ bacteria are detectable beyond day ~38, thus mitigating any impact of persistent infection. Mice then undergo cecal ligation and puncture (CLP). Compellingly, our preliminary data reveal a striking but opposite effect of CD28 blockade on sepsis-induced mortality in the naïve vs. memory models. While treatment of naïve laboratory animals with anti-CD28 resulted in an increase in mortality, treatment of antigen-experienced “memory mice” with anti- CD28 resulted in a significant decrease in mortality as compared to untreated memory controls. Here, we propose to interrogate the mechanisms by which inhibition of CD28-mediated costimulatory signals protects “memory mice” but not naïve laboratory animals from death during sepsis. These studies are significant and highly clinically relevant because they will facilitate the development of immunomodulatory strategies to target the CD28 pathway on physiologically relevant cell types in order to prevent death in septic human patients.