Molecular Basis of cDC1 Development

cDC1 开发的分子基础

• 批准号: 10649736
• 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
• 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/10649736
• 关键词: ATAC-seq; Ablation; 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; Macrophage; Methods; Molecular; Mus; Myelogenous; Myeloid Cells; Output; Pathway interactions; Peptide Initiation Factors; Peptides; Population; Process; Production; Proteins; Publishing; Reagent; Reporter; Reporting; Repression; Role; Route; Signal Induction; Signal Transduction; Site; Specific qualifier value; Suggestion; System; T cell response; T-Cell Activation; Testing; Therapeutic; Time; Tumor-Derived; Vaccines; Viral; Virus; Work; adaptive immune response; design; effector T cell; granulocyte; in vivo; interest; monocyte; novel; progenitor; response; stem cells; tool; transcription factor; tumor; uptake

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.

摘要 对肿瘤和许多病毒的初始适应性免疫反应依赖于CD8T细胞的启动，以产生... 产生能特异性靶向肿瘤或病毒感染细胞的细胞溶解效应T细胞。CD8 T细胞的启动 细胞对这些药物的作用是由一种特殊类型的抗原提呈细胞在体内进行的，这种细胞是 髓系，树突状细胞家族的一员。经典树突状细胞(CDCs)包括 几个密切相关的谱系，明显有别于其他髓系细胞，如巨噬细胞，单核细胞和 细胞或粒细胞。首先，CDC用来激活T细胞，以对抗中枢淋巴管炎的感染。 而不是像其他髓系血统那样在感染部位执行直接效应功能。 疾控中心本身至少由两个主要分支机构组成，现在称为cdc1和cdc2。CDc1 是一个专门摄取和处理细胞相关抗原的谱系，例如来自肿瘤的 病毒感染细胞及其细胞表面与MHC-I分子结合的多肽表位的表达 克洛斯。这种形式的抗原：MHC-I复合体能够激活CD8T细胞，而不是CD4T细胞。这个过程是 叫做交叉演示。CDC2不能与病毒或肿瘤进行交叉演示 活着。CDc1与cDC2有许多遗传和分子上的差异；cDc1需要一套不同的TRAN-TRAN。 CDC2不需要的用于其开发的脚本因素。这包括对运输的依赖- 脚本因子Nfil3、Id2、IRF8和BATF3。我们最近的工作表明，这些面孔之间的遗传等级- TORS以Nfil3为起始因子，通过抑制Id2和BATF3的表达，间接诱导Id2和BATF3的表达。 抑制因子ZEB2。然而，仍然不知道Nfil3是如何被诱导启动这一过程的，以及Nfil3是如何工作的 抑制ZEB2表达。最近，理解这些细节变得重要，因为Clini- 加州大学有兴趣应用Flt3L作为一种治疗方法来扩大cDC1的活体种群。它有 众所周知，Fl3L一般可以扩增树突状细胞，尤其是cDc1。但 我们发现了一个令人惊讶和令人担忧的事实：Flt3L政府将扩大CDC1样细胞，即使在 NFIL3基因缺陷的小鼠，事先完全缺乏cDC1。Nfil3缺陷小鼠中cDC1基因的扩增 Flt3L产生的量与在WT小鼠中的扩张量相同。因此，Flt3L通过一种 与正常的cDC1发育不同的遗传途径。目前还没有测试这种cDC1细胞是否 功能正常，并将增强免疫反应。此应用程序将通过以下方式系统地解决此问题 目的1)定义NFIL3被诱导的正常过程，目的2)定义NFIL3被诱导的机制 驱动cDc1的发展，目标3)确定Flt3诱导的cdc1是否正常工作，并确定 Flt3L在cDC1发育中绕过对Nfil3的正常要求的机制。