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Transcription factor regulation of CD4 and CD8 T cell effector and memory differentiation and function

CD4 和 CD8 T 细胞效应及记忆分化和功能的转录因子调节

基本信息

批准号：
10683256
负责人：
Matthew Eugene Pipkin
金额：
$ 219.19万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10683256
关键词：
Antibody Response B-Lymphocytes Biology CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene CHD7 gene Cells Cellular biology Chromatin Complex Consumption Custom Cytotoxic T-Lymphocytes Data Development Effector Cell Gene Expression Gene Expression Regulation Generations Genes Genetic Epistasis Genetic Screening Genetic Transcription Helper-Inducer T-Lymphocyte Heterogeneity Histone Deacetylase Human IRF4 gene Immunity Intervention Knockout Mice Knowledge Libraries Link Malignant Neoplasms Medical Memory Molecular Nature NuRD complex Paper Pathway interactions Peptide Initiation Factors Population Process Provider RUNX3 gene Regulation Regulator Genes Role System T cell differentiation T cell response T memory cell T-Lymphocyte T-Lymphocyte Subsets Technology Testing Time Tissues Vaccine Design Vaccines Viral Virus Diseases Work adaptive immunity cost effective cytotoxic CD8 T cells effector T cell epigenetic regulation experience experimental study in vivo insight memory CD4 T lymphocyte neoplasm immunotherapy pathogen programs synergism technology development transcription factor tumor vector

项目摘要

ABSTRACT (Overall Component) The three Projects vigorously pursue an understanding of antiviral CD4 and CD8 T cells, linked by the theme: what transcription factors regulate these cells and how do they do so? T cell differentiation into various effector cells, and the capacity to differentiate into memory cells, are important parts of adaptive immunity to pathogens and cancers. Transcription factors (TFs) are central regulators of these differentiation processes. The identification of key TFs regulating different pathways of CD4 and CD8 T cell differentiation have been central to understanding the biology of these cells. However, it is abundantly clear that TFs do not act in isolation and many TFs may be important inducers or repressors of a T cell differentiation pathway. The biggest challenge to studying TF network biology is that experimental manipulation of more than 1 factor at a time under controlled conditions has not been generally feasible, particularly in primary cells in vivo. Therefore, the focus on 1 gene at a time has been an experimental necessity for decades; the generation of double and triple knockout mice is excessively time consuming. Therefore, our approach as a group to this serious problem has been focused on experimental approaches whereby we can modulate and test many genes in parallel for their roles in antiviral T cell responses in vivo, using custom shRNAmir vector-based approaches. We have established these systems, and are able to perform genetic screens, in vivo, in primary CD4 or CD8 T cells, probing differentiation and function. Our projects propose a highly integrated approach to revealing the biology of regulation and differentiation of T follicular helper (Tfh) CD4 T cells, memory CD4 T cells, CTL CD8 T cells, circulating memory CD8 T cells, and tissue-resident CD8 and CD4 T cells (Trm). The three PIs have worked intensively together over the past 5 years to develop important insights into TF biology in T cells. The interactions are not simply via shared cores, they involve extensive shared experiments and ideas regarding TFs, CRs, epigenetics, and gene regulation networks. This is most clearly seen in our 2017 Nature paper on Trm and Runx3. That work is connected to our earlier work together predicting TF regulators of gene expression in T cells, and our most recent paper together, defining the dominant pioneer factor role of Runx3 in the earliest steps of effector CD8 T cell differentiation and defining how Runx3 interacts with other TFs that we have studied, including T-bet, Blimp-1, IRF4, TCF1, and Id2. Our collective experience is that our screens identify multiple critical factors, more than can be comprehensively studied in the context of a single project. Therefore, the equally important challenge—and where our Program’s synergy stands out—is narrowing down the candidate molecules to particular ‘high value’ TFs and CRs that have a major influence on T cell programming. Our three Projects acquire such data in the orthogonal screens and epistasis experiments proposed by each Project, which allow us to converge quickly on important targets to study in detail.

摘要

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

CAR directs T cell adaptation to bile acids in the small intestine.

DOI：
10.1038/s41586-021-03421-6
发表时间：
2021-05
期刊：
Nature
影响因子：
64.8
作者：
Chen ML;Huang X;Wang H;Hegner C;Liu Y;Shang J;Eliason A;Diao H;Park H;Frey B;Wang G;Mosure SA;Solt LA;Kojetin DJ;Rodriguez-Palacios A;Schady DA;Weaver CT;Pipkin ME;Moore DD;Sundrud MS
通讯作者：
Sundrud MS

Cutting Edge: Polycomb Repressive Complex 1 Subunit Cbx4 Positively Regulates Effector Responses in CD8 T Cells.

最前沿：Polycomb 抑制复合物 1 亚基 Cbx4 正向调节 CD8 T 细胞中的效应器反应。

DOI：
10.4049/jimmunol.2200757
发表时间：
2023
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Melo,GuilhermeA;Xu,Tianhao;Calôba,Carolina;Schutte,Alexander;Passos,ThaísO;Neto,MoisésAN;Brum,Gabrielle;Oliveira-Vieira,Bárbara;Higa,Luiza;Monteiro,FábioLL;Berbert,Luiz;Gonçalves,AndréNA;Tanuri,Amilcar;Viola,JoãoPB;We
通讯作者：
We

Structural basis for antibody-mediated neutralization of lymphocytic choriomeningitis virus.

抗体介导的淋巴细胞脉络膜脑膜炎病毒中和的结构基础。

DOI：
10.1016/j.chembiol.2023.03.005
发表时间：
2023
期刊：
Cell chemical biology
影响因子：
8.6
作者：
Moon-Walker,Alex;Zhang,Zeli;Zyla,DawidS;Buck,TierraK;Li,Haoyang;DiazAvalos,Ruben;Schendel,SharonL;Hastie,KathrynM;Crotty,Shane;Saphire,EricaOllmann
通讯作者：
Saphire,EricaOllmann

Runx proteins and transcriptional mechanisms that govern memory CD8 T cell development.