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A novel genetic tool to investigate T cell development and function

一种研究 T 细胞发育和功能的新型遗传工具

基本信息

批准号：
9808399
负责人：
Yongqiang Feng
金额：
$ 26.93万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-22 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9808399
关键词：
Acute Adaptive Immune System Address Adult Animals Area Autoantigens Autoimmune Diseases B cell differentiation B-Lymphocytes Biochemical CD4 Positive T Lymphocytes CRISPR/Cas technology Cell physiology Cells Code Diphtheria Toxin Disease model Dose Elderly Elements Engineering Expression Profiling Frequencies Gene Expression Genetic Genetic Transcription Goals Immune Immune System Diseases Immune Tolerance Immune response Immunologics Immunosuppressive Agents Investigation Knock-in Knowledge Label Lead Life Lymphoid Malignant Neoplasms Mediating Methods Monitor Mouse Strains Multiple Sclerosis Mus Nature Neonatal Organ Peripheral Play Process Proteins Rag1 Mouse Regulator Genes Regulatory T-Lymphocyte Reporter Reporting Research Role Specific qualifier value System T-Cell Development T-Lymphocyte Tamoxifen Technology Testing Therapeutic Time adaptive immunity differentiated B cell diphtheria toxin receptor dosage experimental study genetic element immune activation immune function improved in vivo insight loss of function mouse model novel pathogen postnatal development prevent programs recombinase therapeutic target tool

项目摘要

ABSTRACT The adaptive immune system provides remarkable defense against fast-evolving pathogens. In the meantime, tolerance mechanisms coevolved to prevent deleterious immune responses, among which regulatory T (Treg) cells play a dominant, active role. The adaptive immune system is established during postnatal development through continuous differentiation and egress of T and B cells into the peripheral lymphoid and non-lymphoid organs. It appears that the cells of the adaptive immune system that emerge at the early and late stages of life are programmed differently in their immunological function. Which factors are present at particular stages of life to program the function of immune cells differently is an unsolved mystery. How T and B cells developed at different stages of life respond to specific immunological challenges also remains to be fully explored. Revealing these features of the adaptive immune system will offer us better ways to manipulate immune cells for the treatment of immunological diseases. Genetic tracing tools are needed to address these important questions. However, despite significant progress in the field, tracing and investigating T and B cells emerging at given stages of life remain a technical challenge. To solve this issue, we propose a robust, versatile method to trace T and B cells during their early differentiation in experimental mice. In our preliminary experiments, we have successfully engineered this mouse strain. Specifically, we took advantage of transient Rag1 expression during early T and B cell differentiation and used it to drive the expression of three proteins to trace T and B cells with tamoxifen, to report Rag1 expression with fluorescent protein GFP, and to deplete Rag1-expressing cells with diphtheria toxin when necessary. We have validated all these genetic elements and their functions in the mice. In our proposed research, we will improve our methods to meet various experimental requirements. Furthermore, we will use Treg cells as a proof of concept of our technology in revealing the differential immunosuppressive activity and gene regulatory networks of Treg cells developed at the early and later stages of life in mouse models of autoimmune diseases. In summary, our study generates a robust, versatile genetic toolbox in experimental mice to report, trace, and acutely deplete developing T or B cells when necessary at given stages of life, offering a powerful approach to address many significant questions about adaptive immunity. Our research also produces insights into different Treg functions specified during postnatal development and reveals novel factors and mechanisms controlling Treg-mediated immune tolerance.

摘要