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TCR-dependent activation, functional differentiation and memory formation of CD4+ T cells following infection

感染后 CD4 T 细胞的 TCR 依赖性激活、功能分化和记忆形成

基本信息

批准号：
10077818
负责人：
Matthew A Williams
金额：
$ 48.27万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-17 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10077818
关键词：
Acute Affinity Antigens Automobile Driving Bacterial Infections Biology CD4 Positive T Lymphocytes CD8B1 gene Cell Count Cell Differentiation process Cell physiology Cells Cellular biology Characteristics Clonal Expansion Communicable Diseases Cues Development Effector Cell Frequencies Gene Expression Profile Generations Genetic Transcription Heterogeneity IL2RA gene Immune Immune system Immunity Immunologic Memory Immunotherapeutic agent Infection Lymphoid MHC Class II Genes Malignant Neoplasms Measurement Measures Mediating Memory Modeling Outcome Play Population Receptor Signaling Resolution Role Signal Transduction System T cell differentiation T memory cell T-Cell Activation T-Cell Development T-Cell Receptor T-Lymphocyte T-cell receptor repertoire Testing Therapeutic Tissues Vaccination Vaccines Virus Diseases antigen binding base cytokine design differential expression effector T cell in vivo insight memory CD4 T lymphocyte novel pathogen programs receptor binding response self-renewal therapeutic target tool transcription factor transcriptome

项目摘要

Project Summary Because of their elevated frequency, ability to self-renew and rapid acquisition of effector function following re-activation, memory T cells have an enhanced ability to protect from secondary challenge. The generation of memory T cells is the focal point of numerous vaccine and immunotherapeutic strategies. Most (90-95%) effector T cells die after pathogen clearance, but those fated to become memory cells can be identified during the primary effector response, showing that activated T cells receive differentiation cues during the primary response to infection that influence memory fate differentiation. We have recently shown that T cell receptor (TCR) signals play a key role in driving CD4+ memory T cell differentiation. TCRs that are able to engage MHC Class II-bound antigen (pMHCII) in sustained interactions are biased towards the formation of long-lived memory, while TCRs that engage in short-lived interactions with antigen are biased towards terminal effector cell differentiation. We will build on those studies by using diverse infectious models to define aspects of the TCR-dependent activation and transcriptional program that leads to the formation of lymphoid-resident, circulating and tissue-resident CD4+ memory T cells. We pose three key questions. First, what is the role of TCR signal strength in the formation of memory T cells? We will explore the hypothesis that increasing TCR signal strength in vivo drives terminal effector T cell differentiation, while weaker TCR signal strength allows memory T cell formation. Second, what are the TCR binding parameters associated with memory T cell development? We will measure 2D affinity and bond lifetime with the application of force for TCRs at that are effector-biased or memory-biased. We will test the hypothesis that bond lifetimes will predict TCR-dependent memory differentiation. Third, what are the transcriptional programs that control memory formation? We will test the mechanistic role of molecules that are differentially expressed in memory T cell precursors during the primary effector response, including TCF-1. We anticipate that resolution of the questions posed in this study will provide a framework for determining in greater mechanistic detail how memory T cells form and identify therapeutic approaches for directly modulating CD4+ effector and memory T cell differentiation in vivo.

项目总结