Inflammation-driven T Cell Responses and their Dichotomous Effect on Host Immunity

项目摘要 记忆性CD8 T细胞可以通过T细胞受体(TCR)信号重新激活，但也可以通过促炎细胞因子重新激活。 在没有TCR信号的情况下重新激活被称为旁观者激活，并且已经观察到 涉及多种不同的炎症过程，包括感染、自身免疫和癌症。 旁观者激活的T细胞发挥效应功能并分泌效应分子如颗粒酶B和 干扰素有助于增强宿主免疫力，但也会加剧组织损伤和 防止炎症消退。引发旁观者激活的促炎信号一直是 定义相当清楚，但对抑制或关闭效应器功能的调节信号知之甚少 由旁观者激活的记忆CD8T细胞。相反，负性调节效应器的机制 以TCR依赖的方式重新激活的记忆CD8T细胞的功能已经确立。我们的 初步数据表明，记忆性CD8 T细胞有不同的调节机制 被TCR-VS细胞因子介导的信号重新激活。我们特别建议在 基于组织的免疫反应的背景以确定这些调节系统的扰动 影响病原体清除，以及组织损伤和组织内稳态的重建。最终， 我们的目标是利用所获得的洞察力来开发能够以T细胞为靶向的治疗策略。 介导的组织损伤。

Project Summary Memory CD8 T cells can be reactivated by a T cell receptor (TCR) signal, but also pro-inflammatory cytokines. Reactivation in the absence of a TCR signal is referred to as bystander-activation and has been observed across a wide range of different inflammatory processes, including infections, autoimmunity and cancer. Bystander activated T cell exert effector function and secrete effector molecules such as granzyme B and interferon gamma, which contribute to enhancing host immunity, but also exacerbate tissue damage and prevent resolution of inflammation. The pro-inflammatory signals that elicit bystander activation have been fairly well defined, but little is known regarding the regulatory signals that can inhibit or turn off effector function by bystander activated memory CD8 T cells. In contrast, the mechanisms that negatively regulate effector function of memory CD8 T cells that are reactivated in a TCR-dependent manner are well established. Our preliminary data suggest that there are distinct regulatory mechanisms in place for memory CD8 T cells reactivated by TCR- vs. cytokine-mediated signals. We specifically propose to study these mechanisms in the context of tissue-based immune responses to determine how a perturbation of these regulatory systems affects pathogen clearance, as well as tissue damage and re-establishing of tissue homeostasis. Ultimately, our goal is to use the gained insights to develop strategies that will allow for therapeutic targeting of T cell- mediated tissue damage.