Impairment and recovery of CD8 T cell responses after sepsis

 描述(由申请人提供)：在感染或接种后发展和维持记忆CD8 T细胞的能力是适应性免疫反应的标志，也是预防传染病或癌症免疫治疗的保护性疫苗的基础。由于对感染的保护程度取决于抗原(Ag)再次暴露时存在的记忆性CD8 T细胞的功能特征(质量)和数量(数量)，因此了解控制幼稚到记忆性CD8 T细胞分化和记忆性CD8 T细胞池的长期维持的机制对于实现最大限度的保护至关重要。病毒或细菌感染的结果是由病原体和受感染宿主之间一系列复杂的相互作用决定的。在这些相互作用中，宿主在感染时的免疫状态可以对宿主对疾病的易感性产生重大影响。在大多数重症监护病房，多菌败血症是导致死亡的主要原因，而在脓毒症中幸存下来的患者往往表现出免疫功能严重受损，先天性和获得性免疫反应缺陷。在多菌败血症期间观察到的普遍免疫抑制的一个特征是T细胞免疫力下降。因此，败血症患者和败血症幸存者很容易受到新的或以前遇到的感染的影响，当存在正常的、起作用的免疫系统时，这些感染很容易被T细胞控制。在这方面，我们最近的论文显示，脓毒症显著损害了宿主的 在全身性和局部性模型感染的背景下，装载对新引入的抗原的最佳CD8T细胞反应。我们在这些出版物中的数据还揭示了脓毒症在塑造感染的数量和功能方面以前没有被认识到的作用-或者 疫苗诱导的预先存在的记忆CD8 T细胞。然而，脓毒症引起的幼稚和记忆性CD8 T细胞池的改变程度以及控制其恢复、长期维持和分化的机制，以及恢复脓毒症幸存者幼稚和记忆CD8 T细胞数量和/或功能的潜在治疗干预措施目前尚不清楚。因此，我们的长期目标是充分了解脓毒症诱导后对幼稚和先前存在的记忆CD8 T细胞群施加的功能后果。我们的中心假设是，脓毒症诱导的抗原特异性幼稚和/或记忆性CD8T细胞的凋亡导致CD8T细胞反应的组成和/或功能的长期有害变化，最终导致CD8T细胞对局部和全身感染背景下新遇到的或以前遇到的抗原的反应减弱。我们将通过以下具体目标来解决我们的长期目标：目标1-确定树突状细胞在脓毒症诱导的CD8 T细胞对新引入的抗原的免疫损伤中的调节作用。目的2-确定脓毒症后CD8T细胞内在因子控制原发CD8T细胞反应的程度。目的3-确定脓毒症对原有记忆CD8 T细胞反应的维持和功能的影响。

 DESCRIPTION (provided by applicant): The ability to develop and sustain memory CD8 T cells post-infection or vaccination is a hallmark of the adaptive immune response and the basis for protective vaccination against infectious disease or in cancer immunotherapy. Since the degree of protection to infection depends on the functional characteristics (quality) and number (quantity) of memory CD8 T cells present at the time of antigen (Ag) re-exposure, understanding the mechanisms that govern naïve-to-memory CD8 T cell differentiation and long-term maintenance of the memory CD8 T cell pool are critical for achieving maximal protection. The outcome of viral or bacterial infections is determined by a series of complex interactions between the pathogen and infected host. Among these interactions the immune status of the host at the time of infection can have a major impact in the host susceptibility to disease. Polymicrobial sepsis represents a leading cause of death in most intensive care units, and patients who survive sepsis often display severely compromised immune function with deficits in innate and adaptive immune responses. One hallmark of the general immune suppression observed during polymicrobial sepsis is diminished T cell immunity. Consequently, septic patients and sepsis survivors are highly susceptible to new or previously encountered infections that are readily controlled by T cells when a normal, functioning immune system is present. In this regard, our recent papers revealed that sepsis significantly compromises the host's ability to mount optimal CD8 T cell responses to newly introduced Ag presented in the context of systemic and localized model infections. Our data in these publications also revealed a previously unappreciated role for sepsis in shaping the quantity and functionality of infection- or vaccine-induced pre-existing memory CD8 T cells. However, the extent of sepsis-induced changes the naïve and memory CD8 T cell pool and mechanisms that control their recovery, long-term maintenance and differentiation as well as potential therapeutic interventions to restore number and/or function of naïve and memory CD8 T cells in sepsis survivors are currently unknown. Thus, our long-term goal is to fully understand the functional consequences imposed on naïve and pre-existing memory CD8 T cell populations following sepsis induction. Our central hypothesis is that sepsis-induced apoptosis of Ag-specific naïve and/or memory CD8 T cells leads to long-lasting deleterious changes in the composition and/or function of CD8 T cell responses that ultimately result in diminished CD8 T cell responses to newly or previously encountered Ag delivered in the context of localized and systemic infections. We will address our long-term goal with the following specific aims: Aim 1 - Define the regulatory role of dendriti cells in sepsis-induced impairment of CD8 T cell immunity to newly introduced antigens. Aim 2 - Determine the extent to which CD8 T cell intrinsic factors control primary CD8 T cell responses after sepsis. Aim 3 - Determine the impact of sepsis on maintenance and function of pre-existing memory CD8 T cell responses.