Memory T Cell Cosigning Pathways in Sepsis-Induced Immune Dysregulation

摘要/摘要 最近评估脓毒症患者免疫表型和功能的研究增加了我们的 了解脓毒症时发生的免疫失调。新的范式表明， T细胞共刺激和共抑制分子的平衡是决定T细胞转归的关键 脓毒症时的激活和/或调节失调。一种对T细胞最关键的共刺激分子 激活的是CD28。CD28是一种强大的共刺激受体，在幼稚T细胞上是必需的二级信号 这促进了T细胞的最佳激活。在脓毒症期间，CD28在CD4+上的表达下调 小鼠和人类的CD8+T细胞。这些表达数据导致了CD28的假设 脓毒症后的免疫抑制可能与下调有关。然而，CD28的功能作用 在脓毒症期间是有争议的，因为其他研究已经显示CD28阻断在几个 脓毒症小鼠模型。值得注意的是，CD28在幼稚T细胞和记忆性T细胞上的表达存在差异。此外， 即使是保留CD28表达的记忆T细胞也可能减少了对CD28信号的依赖 激活。这一点很重要，因为记忆T细胞约占人类T细胞室的50% 到大多数人成年的时候，但在实验室小鼠身上出现的几率要少得多(5%)。因此，我们 假设CD28在脓毒症过程中的相互矛盾的报道和不清楚的作用可能是由于差异所致 记忆中的作用与幼稚的T细胞。为了检验这一假说并更好地模拟抗原经验 人类患者的免疫系统，在上一个资助周期中，我们开发了一个模型来产生小鼠 拥有一个更类似于成年人的记忆T细胞室，然后可以被呈现出来 败血症。这项研究最近发表在JCI Insight上。简而言之，幼稚的动物被顺序感染了 不同的敏锐清除细菌和病毒感染。这种方法产生的小鼠有~20%的CD4+和 ~60%的CD8+记忆T细胞，但实际感染完全消除，没有病毒/细菌 可在~38天后检测到，从而减轻持续感染的任何影响。然后小鼠接受盲肠结扎 和穿刺术(CLP)。令人信服的是，我们的初步数据揭示了CD28封锁的惊人但相反的效果 关于幼稚与记忆模型中脓毒症所致死亡率的比较。在治疗幼稚的实验动物时 抗CD28导致死亡率增加，用抗-CD28治疗抗原经历过的“记忆小鼠” 与未经治疗的记忆对照组相比，CD28导致死亡率显著下降。在这里，我们 建议询问抑制CD28介导的共刺激信号保护的机制 “记忆小鼠”，但不是幼稚的实验动物在脓毒症期间死亡。这些研究很有意义，而且 高度临床相关性，因为它们将促进免疫调节策略的发展，以靶向 CD28途径在生理相关细胞类型上的作用，以防止败血症患者的死亡。

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.