Molecular Basis of cDC1 Development

cDC1 开发的分子基础

基本信息

批准号：
10450553
负责人：
Kenneth M Murphy
金额：
$ 55.99万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-17 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10450553
关键词：
ATAC-seq Address Antigen-Presenting Cells Antigens Binding Bypass CCAAT-Enhancer-Binding Proteins CD8-Positive T-Lymphocytes CRISPR/Cas technology Cell physiology Cell surface Cells ChIP-seq Chimeric Proteins Clinical Complex Critiques Cross Presentation Data Dendritic Cells Dependence Development Elements Enhancers Epitopes Exhibits FLT3 gene FLT3 ligand Family member Gene Targeting Generations Genes Genetic Genetic Transcription Goals Homeostasis Human Immune response Immunity In Vitro Infection Literature Lymphoid Tissue MHC antigen Methods Mole the mammal Molecular Molecular Genetics Mus Myelogenous Myeloid Cells Output Pathway interactions Peptides Population Process Production Proteins Publishing Reagent Reporter Reporting Role Route Signal Transduction Site Specific qualifier value Suggestion System T cell response T-Lymphocyte Testing Therapeutic Time Tumor-Derived Vaccines Viral Virus Work adaptive immune response design effector T cell granulocyte in vivo interest macrophage novel progenitor response stem cells tool transcription factor tumor uptake

ATAC-seq Address Antigen-Presenting Cells Antigens Binding Bypass CCAAT-Enhancer-Binding Proteins CD8-Positive T-Lymphocytes CRISPR/Cas technology Cell physiology Cell surface Cells ChIP-seq Chimeric Proteins Clinical Complex Critiques Cross Presentation Data Dendritic Cells Dependence Development Elements Enhancers Epitopes Exhibits FLT3 gene FLT3 ligand Family member Gene Targeting Generations Genes Genetic Genetic Transcription Goals Homeostasis Human Immune response Immunity In Vitro Infection Literature Lymphoid Tissue MHC antigen Methods Mole the mammal Molecular Molecular Genetics Mus Myelogenous Myeloid Cells Output Pathway interactions Peptides Population Process Production Proteins Publishing Reagent Reporter Reporting Role Route Signal Transduction Site Specific qualifier value Suggestion System T cell response T-Lymphocyte Testing Therapeutic Time Tumor-Derived Vaccines Viral Virus Work adaptive immune response design effector T cell granulocyte in vivo interest macrophage novel progenitor response stem cells tool transcription factor tumor uptake

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项目摘要

ABSTRACT The initial adaptive immune response to tumors and many viruses relies on the priming of CD8 T cells to gen- erate cytolytic effector T cells that can specifically target tumors or virally infected cells. The priming of CD8 T cells to these agents is carried out in vivo by a particular type of antigen presenting cell that is a component of the myeloid system and a member of the family of dendritic cells. Classical dendritic cells (cDCs) comprise several closely related lineages that are clearly distinct from other myeloid cells such as macrophages, mono- cytes or granulocytes. Primarily, cDCs serve to activate T cells against infections in the central lymphoid tis- sues, rather than carrying out direct effector functions at sites of infections as the other myeloid lineages do. The cDCs are themselves comprised of at least two major branches, now called cDC1 and cDC2. The cDC1 is a lineage that specializes in the uptake and processing of cell-associated antigens, such as from tumors of virally infected cells and the expression of peptide epitopes on its cell surface in conjunction with MHC-I mole- cules. This form of antigen:MHC-I complex is able to activate CD8 T cells, and not CD4 T cells. This process is called cross-presentation. The cDC2 is not capable of carrying out cross-presentation to viruses or tumors in vivo. The cDC1 has many genetic and molecular differences from cDC2; cDC1 require a distinct set of tran- scription factors for their development that are not required for cDC2. This includes dependence on the tran- scription factors Nfil3, Id2, Irf8 and Batf3. Our recent work showed that the genetic hierarchy among these fac- tors has Nfil3 as the first and initiating factor, acting to indirectly induce Id2 and Batf3 via the suppression of the repressor Zeb2. However, it is still unknown how Nfil3 is induced to initiate this process, and how Nfil3 works to suppress Zeb2 expression. It has recently become important to understand these details because of the clini- cal interest to apply Flt3L administration as a therapeutic in expanding the in vivo population of cDC1. It has been known for some time that Fl3L can expand dendritic cells in general and expand cDC1 in particular. But we have uncovered a surprising and worrisome fact; Flt3L administration will expand cDC1-like cells even in Nfil3-deficient mice, which completely lack cDC1 beforehand. The expansion of cDC1 in Nfil3-deficent mice produced by Flt3L is of the same magnitude as the expansion in WT mice. Thus, Flt3L is inducing cDC1 by a different genetic route than normal cDC1 development. There has been no test of whether such cDC1 cells function normally and will boost an immune response. This application will systematically address this issue by Aim 1) defining the normal process by which Nfil3 is induced, Aim 2) define the mechanism by which NFIL3 drives cDC1 development, and Aim 3) determine whether Flt3-induced cDC1 function normally and determine the mechanism by which Flt3L bypasses the normal requirement for Nfil3 in cDC1 development.

抽象的对肿瘤和许多病毒的最初适应性免疫反应依赖于CD8 T细胞的启动可以专门针对肿瘤或病毒感染细胞的细胞溶解效应T细胞。 CD8 T的启动这些药物的细胞是由特定类型的抗原呈现细胞进行体内进行的，该细胞是髓样系统和树突状细胞家族的成员。经典树突状细胞（CDC）包含几种与其他髓样细胞明显不同的密切相关的谱系，例如巨噬细胞细胞或粒细胞。主要是，CDC用于激活T细胞，以针对中央淋巴机中的感染进行感染起诉，而不是像其他髓样谱系那样在感染部位执行直接效应子功能。 CDC本身由至少两个主要分支组成，现在称为CDC1和CDC2。 CDC1 是专门研究细胞相关抗原的谱系，例如来自病毒感染的细胞和肽表现在其细胞表面的表达与MHC-1摩尔 - Cules。这种形式的抗原：MHC-1复合物能够激活CD8 T细胞，而不是CD4 T细胞。这个过程是称为交叉表现。 CDC2无法在病毒或肿瘤中进行交叉呈递体内。 CDC1具有许多与Cdc2的遗传和分子差异。 CDC1需要一组不同的tran- CDC2不需要开发的录音因素。这包括对tran的依赖 Scription因子NFIL3，ID2，IRF8和BATF3。我们最近的工作表明，在这些方面的遗传层次结构 TOR具有NFIL3作为第一个且引发因素，通过抑制来间接诱导ID2和BATF3 阻遏ZEB2。但是，仍然未知NFIL3是如何引起该过程的，以及NFIL3如何工作抑制Zeb2表达。由于临床，了解这些细节已经变得很重要将FLT3L给药应用于扩大CDC1体内种群的治疗性的利益。它有一段时间以来，FL3L通常会扩大树突状细胞，尤其是扩展CDC1。但我们发现了一个令人惊讶和令人担忧的事实。即使在 NFIL3缺陷小鼠，事先完全缺乏CDC1。 Cdc1在NFIL3缺乏小鼠中的扩展由FLT3L产生的大小与WT小鼠的膨胀相同。因此，FLT3L通过A诱导Cdc1 与正常CDC1发育不同的遗传途径。没有测试这种CDC1细胞是否正常功能，将增强免疫反应。此应用程序将通过目标1）定义诱导NFIL3的正常过程，目标2）定义NFIL3的机制驱动CDC1开发，目标3）确定FLT3诱导的CDC1是否正常功能并确定 FLT3L绕过CDC1发育中NFIL3的正常需求的机制。