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

炎症驱动的 T 细胞反应及其对宿主免疫的二分效应

基本信息

批准号：
10682491
负责人：
Martin Prlic
金额：
$ 52.8万
依托单位：
FRED HUTCHINSON CANCER CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10682491
关键词：
Affect Agonist Antigens Autoimmunity Biological Models Blood CD8-Positive T-Lymphocytes Cell Separation Chronic Data Disease Dose Ensure Equilibrium Exertion Exposure to Failure Goals Granzyme Homeostasis Human Human Herpesvirus 2 IL18 gene Immune response Immunity Impairment Infection Inflammation Inflammatory Interferon Type II Interleukin-12 Interleukin-15 Listeria monocytogenes LoxP-flanked allele Malignant Neoplasms Mediating Memory Modeling Mucositis Mucous Membrane Nature Pathology Predisposition Process Property Receptor Signaling Resolution Signal Induction Signal Transduction Stimulus System T cell response T cell therapy T memory cell T-Cell Activation T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets Tamoxifen Testing Therapeutic Time Tissues Transforming Growth Factor beta Viral Work acute infection chronic infection cytokine effector T cell experimental study insight mouse model novel pathogen prevent receptor receptor-mediated signaling virtual

项目摘要

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.

项目摘要记忆性CD 8 T细胞可以通过T细胞受体（TCR）信号再活化，但也可以通过促炎细胞因子再活化。在TCR信号不存在的情况下的再活化被称为旁观者活化，并且已经观察到在广泛的不同炎症过程中，包括感染，自身免疫和癌症。旁观者活化的T细胞发挥效应子功能并分泌效应子分子，如颗粒酶B和干扰素γ有助于增强宿主免疫力，但也加剧组织损伤，防止炎症消退。引起旁观者激活的促炎信号已经被相当明确的，但很少有人知道有关的调节信号，可以抑制或关闭效应器功能通过旁观者激活的记忆性CD 8 T细胞。相反，负调节效应子的机制以TCR依赖性方式再活化的记忆性CD 8 T细胞的功能已被充分确立。我们初步数据表明，记忆性CD 8 T细胞存在不同的调节机制，由TCR- vs.甘氨酸介导的信号重新激活。我们特别建议研究这些机制，背景下的组织为基础的免疫反应，以确定如何扰动这些调节系统影响病原体清除以及组织损伤和组织稳态的重建。最后，我们的目标是利用所获得的见解来开发策略，以允许治疗靶向T细胞，介导的组织损伤。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Human Tumor-Infiltrating MAIT Cells Display Hallmarks of Bacterial Antigen Recognition in Colorectal Cancer.

DOI：
10.1016/j.xcrm.2020.100039
发表时间：
2020-06-23
期刊：
Cell reports. Medicine
影响因子：
0
作者：
Li S;Simoni Y;Becht E;Loh CY;Li N;Lachance D;Koo SL;Lim TP;Tan EKW;Mathew R;Nguyen A;Golovato J;Berkson JD;Prlic M;Lee B;Minot SS;Nagarajan N;Dey N;Tan DSW;Tan IB;Newell EW
通讯作者：
Newell EW

OMIP-070: NKp46-Based 27-Color Phenotyping to Define Natural Killer Cells Isolated From Human Tumor Tissues.

DOI：
10.1002/cyto.a.24230
发表时间：
2020-10
期刊：
Cytometry. Part A : the journal of the International Society for Analytical Cytology
影响因子：
0
作者：
Frutoso M;Mair F;Prlic M
通讯作者：
Prlic M

OMIP-102: 50-color phenotyping of the human immune system with in-depth assessment of T cells and dendritic cells.

OMIP-102：对 T 细胞和树突细胞进行深入评估，对人体免疫系统进行 50 色表型分析。

DOI：
10.1002/cyto.a.24841
发表时间：
2024
期刊：
Cytometry. Part A : the journal of the International Society for Analytical Cytology
影响因子：
0
作者：
Konecny,AndrewJ;Mage,PeterL;Tyznik,AaronJ;Prlic,Martin;Mair,Florian
通讯作者：
Mair,Florian

The Ugly Duckling Turned to Swan: A Change in Perception of Bystander-Activated Memory CD8 T Cells.