Impairment and recovery of CD8 T cell responses after sepsis

 描述（由申请方提供）：感染或接种后形成和维持记忆性CD 8 T细胞的能力是适应性免疫应答的标志，也是针对感染性疾病或癌症免疫治疗的保护性疫苗接种的基础。由于对感染的保护程度取决于抗原（Ag）再暴露时存在的记忆性CD 8 T细胞的功能特征（质量）和数量（数量），因此了解控制幼稚至记忆性CD 8 T细胞分化的机制以及记忆性CD 8 T细胞库的长期维持对于实现最大保护至关重要。病毒或细菌感染的结果是由病原体和受感染宿主之间的一系列复杂相互作用决定的。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中，多微生物败血症是死亡的主要原因，败血症存活的患者通常表现出严重受损的免疫功能，先天性和适应性免疫应答不足。在多微生物脓毒症期间观察到的一般免疫抑制的一个标志是T细胞免疫力降低。因此，脓毒症患者和脓毒症幸存者非常容易受到新的或以前遇到的感染，当存在正常的功能性免疫系统时，这些感染很容易被T细胞控制。在这方面，我们最近的论文揭示，脓毒症显著损害宿主的能力， 在系统性和局部模型感染的背景下，对新引入的Ag产生最佳的CD 8 T细胞应答。我们在这些出版物中的数据还揭示了脓毒症在影响感染的数量和功能方面的一个以前未被认识到的作用， 疫苗诱导的预先存在的记忆性CD 8 T细胞。然而，脓毒症诱导的幼稚和记忆性CD 8 T细胞库变化的程度，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中幼稚和记忆性CD 8 T细胞数量和/或功能的潜在治疗干预目前尚不清楚。因此，我们的长期目标是充分了解脓毒症诱导后对幼稚和预先存在的记忆CD 8 T细胞群的功能影响。我们的中心假设是，脓毒症诱导的Ag特异性幼稚和/或记忆CD 8 T细胞的凋亡导致CD 8 T细胞应答的组成和/或功能的长期有害变化，最终导致CD 8 T细胞对局部和全身感染背景下递送的新的或先前遇到的Ag的应答减少。我们将解决我们的长期目标与以下具体目标：目标1 -定义树突状细胞在脓毒症诱导的CD 8 T细胞免疫力受损的调节作用，以新引入的抗原。目的2 -确定脓毒症后CD 8 T细胞内在因子控制原发性CD 8 T细胞应答的程度。目的3 -确定脓毒症对预先存在的记忆性CD 8 T细胞应答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.