Costimulatory Signals in CD4+ T Cell Activation

CD4 T 细胞激活中的共刺激信号

基本信息

批准号：
10373960
负责人：
Marc Kevin Jenkins
金额：
$ 46.66万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
1989
资助国家：
美国
起止时间：
1989-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10373960
关键词：
Acute Affinity Antigen-Presenting Cells Autoimmunity B-Lymphocytes Back CD28 gene CD4 Positive T Lymphocytes Cells Clonal Expansion Consumption Development Effector Cell Epitopes FOXP3 gene Family Funding Gene Targeting Goals Graft Rejection Grant Helper-Inducer T-Lymphocyte IL2RA gene Immune Immune response Immunity Immunology Immunotherapy Infection Interleukin 2 Receptor Interleukin-2 Knowledge Lead Light Malignant Neoplasms Memory Methods Microbe Modeling Monitor Mus Mutation Pathway interactions Peptides Play Population Process Receptor Signaling Regulatory T-Lymphocyte Research Role Signal Transduction Site Specificity T-Cell Activation T-Cell Receptor T-Lymphocyte Tail Testing Thymus Gland Work antimicrobial immune self tolerance insight member mutant new technology novel receptor response retroviral transduction secondary lymphoid organ transplantation therapy

项目摘要

Project Summary/Abstract The two-signal model in which an antigen-presenting cell-derived costimulatory signal, epitomized by CD28, is needed for T cells to respond maximally to T cell receptor (TCR) stimulation is now part of the immunology canon and fueled exciting immunotherapies for transplant rejection, autoimmunity, and cancer. Most of the advances in the costimulation field, however, applied to conventional Foxp3neg CD4+ T cells. Although CD28 enhances the development of Foxp3+ regulatory (Treg) cells as they are selected by high affinity TCR recognition of self peptides in the thymus, and is required for their autoimmunity-suppressing functions, much less is known about the costimulatory requirements of Treg cells as they participate in immune responses to foreign peptides. During the last funding period, we found that the pre-immune repertoires of CD4+ T cells specific for foreign peptides from microbes contain both conventional AND Treg cells. Both populations underwent clonal expansion in the secondary lymphoid organs after infection with a microbe expressing the relevant peptide but the two populations formed different types of effector cells and generated memory cells with different efficiencies. Our results lead to the remarkable conclusion that two parallel CD4+ T cell repertoires exist for each foreign peptide – one composed of conventional naïve cells and a smaller one composed of Treg cells. Almost nothing is known about the signals that govern the activation of foreign peptide-specific Treg cells during immune responses to infection or their interactions with conventional T cells responding to the same peptide. The goal of this project is to determine whether foreign peptide-specific Treg cells require CD28 costimulation during immune responses to infection and if so understand the signal transduction process. We will also test the intriguing possibility that foreign peptide-specific Treg cells play special roles in regulating the expansion and differentiation of the conventional T cells specific for the same peptide as both populations respond during infection. This research could shed light on the understudied role that Treg cells play during infection and provide new uses for modulation of T cell costimulation.

项目概要/摘要双信号模型，其中抗原呈递细胞衍生的共刺激信号（以 CD28 为代表）是 T 细胞对 T 细胞受体 (TCR) 刺激做出最大反应所需的 T 细胞现在已成为免疫学的一部分经典并推动了针对移植排斥、自身免疫和癌症的令人兴奋的免疫疗法。然而，共刺激领域的进展应用于传统的 Foxp3neg CD4+ T 细胞，尽管 CD28。增强 Foxp3+ 调节性 (Treg) 细胞的发育，因为它们是通过高亲和力 TCR 选择的胸腺中自身肽的识别，并且是其自身免疫抑制功能所必需的人们对 Treg 细胞参与免疫反应的共刺激要求知之甚少。外来肽。在上一个资助期间，我们发现 CD4+ T 细胞特异性的免疫前库来自微生物的外源肽同时含有常规细胞和 Treg 细胞，两个群体都存活下来。感染表达相关基因的微生物后，次级淋巴器官中的克隆扩增肽，但两个群体形成了不同类型的效应细胞并产生了记忆细胞我们的结果得出了两个平行的 CD4+ T 细胞库的显着结论。每一种外源肽都存在——一个由传统的初始细胞组成，另一个较小的由 Treg 组成关于控制外源肽特异性 Treg 细胞激活的信号几乎一无所知。在对感染的免疫反应或它们与传统 T 细胞相互作用的过程中该项目的目标是确定外源肽特异性 Treg 细胞是否需要 CD28。对感染的免疫反应期间的共刺激，如果是的话，了解信号转导过程。还将测试外源肽特异性 Treg 细胞在调节两个群体对相同肽具有特异性的常规 T 细胞的扩增和分化这项研究可以揭示 Treg 细胞在感染过程中所发挥的作用。感染并为调节 T 细胞共刺激提供新用途。