Non-Canonical Cross-presentation in Dendritic Cells Upon TAP Blockade

TAP 阻断后树突状细胞中的非典型交叉呈递

基本信息

项目摘要

 DESCRIPTION (provided by applicant): The classic pathway of major histocompatibility complex class I (MHC-I) presentation is important for activation of CD8 T cells, and relies primarily on shuttling cytosolic peptides into the endoplasmic reticulum (ER) lumen by the transporter associated with antigen processing (TAP). This critical role of TAP has made it a prime target for blockade by several human viruses and downregulation in many cancers as a mechanism of evading detection by cytotoxic CD8 T cells. There are, however, other mechanisms of MHC-I presentation that bypass TAP and activate TAP-independent CD8 T cell responses. One of these is cross-presentation, where dendritic cells present peptides derived from extracellular antigens. Although TAP can be important here, cross- presentation can also take place without TAP, but the pathways involved are poorly defined. There are many disease states that result from altered TAP function and their basis is not easily explained by impairment in classic MHC-I presentation. TAP polymorphisms are associated with an increased risk for systemic lupus erythematosus (SLE), a chronic and severe systemic autoimmune disease characterized by high titers of autoantibodies against cellular constituents. TAP mutations in humans lead to TAP deficiency syndrome where surprisingly patients do not exhibit particular susceptibility to viruses but rather suffer from chronic inflammation. Finally, the successful eradication of smallpox is attributed to vaccination with cowpox virus that was recently unexpectedly shown to block TAP. Over the years, we have made significant contributions to understanding the cell biology and regulation of antigen presentation. Using genetic, cell biological, and biochemical approaches, we will pursue 3 aims seeking to delineate the pathways of TAP-independent cross-presentation: Aim 1: We have found that MHC-I reside in special compartments within dendritic cells and their trafficking from these compartments to sites of microbial antigen is regulated by Toll-like receptors, which detect microbial components. We will study how absent TAP impacts the cellular localization and trafficking of MHC-I molecules. Aim 2: We have shown that Toll-like receptors favor the cross-presentation of microbial over self-antigens. We will investigate whether cross-presentation in the absence of TAP is subject to regulation by these receptors. Aim 3: We will study the cross-presentation of both infectious viral and non-infectious cellular antigens by virally infected dendritic cells wher TAP function is impaired. We would like to know whether cross- presentation can rescue MHC-I presentation of viral antigens by the very cells that are infected. We will also determine the ability of these infected cells to confine this presentation to viral and not cellular antigens. Or basic research here will enable us to identify critical points of regulation in the pathways of MHC-I presentation. We will then be able to design better vaccines for infectious diseases like malaria, tuberculosis or HIV that are best controlled by CD8 T cells. We will also be able to design strategies for intervention in autoimmune diseases like lupus where the presentation of cellular antigens is dysregulated.
 描述(由申请人提供): 主要组织相容性复合物I类(MHC-I)呈递的经典途径对于CD 8 T细胞的活化是重要的,并且主要依赖于通过与抗原加工相关的转运蛋白(TAP)将胞质肽穿梭到内质网(ER)腔中。TAP的这种关键作用使其成为几种人类病毒阻断的主要靶标,并在许多癌症中下调,作为逃避细胞毒性CD 8 T细胞检测的机制。然而,存在绕过TAP并激活TAP非依赖性CD 8 T细胞应答的MHC-I呈递的其他机制。其中之一是交叉呈递,其中树突细胞呈递源自细胞外抗原的肽。虽然TAP在这里可能很重要,但交叉呈递也可以在没有TAP的情况下发生,但所涉及的途径定义不清。许多疾病状态是由TAP功能改变引起的,其基础并不容易通过经典MHC-I表现的损伤来解释。TAP多态性与系统性红斑狼疮(SLE)的风险增加有关,SLE是一种慢性和严重的系统性自身免疫性疾病,其特征是针对细胞成分的高滴度自身抗体。人类的TAP突变导致TAP缺乏综合征,令人惊讶的是,患者对病毒没有表现出特别的易感性,而是患有慢性炎症。最后,天花的成功根除归功于牛痘病毒的接种,最近出乎意料地显示牛痘病毒可以阻断TAP。多年来,我们为理解细胞生物学和抗原呈递的调节做出了重大贡献。使用遗传学,细胞生物学和生物化学的方法,我们将追求3个目标,寻求描绘TAP独立的交叉呈递的途径:目的1:我们已经发现,MHC-I驻留在树突状细胞内的特殊隔室和它们的运输从这些隔室的微生物抗原的网站是由Toll样受体,检测微生物成分的调节。我们将研究缺少TAP如何影响MHC-I分子的细胞定位和运输。目的2:我们已经证明Toll样受体有利于微生物对自身抗原的交叉呈递。我们将调查是否在TAP的情况下交叉呈递受这些受体的调节。目标三:我们将研究TAP功能受损的病毒感染树突状细胞对感染性病毒和非感染性细胞抗原的交叉呈递。我们想知道交叉呈递是否可以拯救被感染细胞对病毒抗原的MHC-I呈递。我们还将确定这些受感染细胞将这种呈递限于病毒而非细胞抗原的能力。 或者基础研究将使我们能够确定MHC-I呈递途径中的关键调控点。然后,我们将能够设计出更好的疫苗,用于疟疾、结核病或艾滋病等传染病,这些疾病最好由CD 8 T细胞控制。我们还将能够设计干预自身免疫性疾病的策略,如狼疮,其中细胞抗原的呈递失调。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Julie Magarian Blander其他文献

Julie Magarian Blander的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Julie Magarian Blander', 18)}}的其他基金

Mobilizing TAP-independent CD8 T cells through non-canonical cross-presentation
通过非规范交叉呈递动员不依赖 TAP 的 CD8 T 细胞
  • 批准号:
    10659785
  • 财政年份:
    2023
  • 资助金额:
    $ 41.93万
  • 项目类别:
Modulating XIAP for the Treatment of Inflammatory Bowel Disease
调节 XIAP 治疗炎症性肠病
  • 批准号:
    10727185
  • 财政年份:
    2023
  • 资助金额:
    $ 41.93万
  • 项目类别:
Toll-like receptor control of endocytic antigen cross-presentation
Toll 样受体控制内吞抗原交叉呈递
  • 批准号:
    10735354
  • 财政年份:
    2023
  • 资助金额:
    $ 41.93万
  • 项目类别:
Toll-like Receptor Control of MHC Class I Endocytosis
MHC I 类内吞作用的 Toll 样受体控制
  • 批准号:
    10557150
  • 财政年份:
    2022
  • 资助金额:
    $ 41.93万
  • 项目类别:
Toll-like Receptor Control of MHC Class I Endocytosis
MHC I 类内吞作用的 Toll 样受体控制
  • 批准号:
    10453097
  • 财政年份:
    2022
  • 资助金额:
    $ 41.93万
  • 项目类别:
Innate and Adaptive Immune Consequences of Necroptosis
坏死性凋亡的先天性和适应性免疫后果
  • 批准号:
    10196978
  • 财政年份:
    2020
  • 资助金额:
    $ 41.93万
  • 项目类别:
Innate and Adaptive Immune Consequences of Necroptosis
坏死性凋亡的先天性和适应性免疫后果
  • 批准号:
    10043494
  • 财政年份:
    2020
  • 资助金额:
    $ 41.93万
  • 项目类别:
Role of apoptosis in the intestinal epithelium during homeostasis and disease
肠上皮细胞凋亡在稳态和疾病过程中的作用
  • 批准号:
    9926879
  • 财政年份:
    2017
  • 资助金额:
    $ 41.93万
  • 项目类别:
Novel vita-vaccine formula combines safety of dead and efficacy of live vaccines
新型维生素疫苗配方结合了死疫苗的安全性和活疫苗的功效
  • 批准号:
    9357501
  • 财政年份:
    2016
  • 资助金额:
    $ 41.93万
  • 项目类别:
Control of protective immunity by innate pathways sensing bacterial viability
通过感知细菌活力的先天途径控制保护性免疫
  • 批准号:
    8295078
  • 财政年份:
    2012
  • 资助金额:
    $ 41.93万
  • 项目类别:

相似海外基金

Defining MHC class I restricted antigen presentation to CD8 T cells in experimental AD and Tauopathy - Supplement
定义实验性 AD 和 Tau 病中 MHC I 类限制性抗原呈递至 CD8 T 细胞 - 补充
  • 批准号:
    10836880
  • 财政年份:
    2023
  • 资助金额:
    $ 41.93万
  • 项目类别:
Targeting MAL2-mediated endocytosis to enhance tumor cell antigen presentation
靶向 MAL2 介导的内吞作用以增强肿瘤细胞抗原呈递
  • 批准号:
    10734324
  • 财政年份:
    2023
  • 资助金额:
    $ 41.93万
  • 项目类别:
Antigen presentation to the adaptive immune system in the choroid contributes to ocular autoimmune disease
脉络膜中的适应性免疫系统的抗原呈递导致眼部自身免疫性疾病
  • 批准号:
    10740465
  • 财政年份:
    2023
  • 资助金额:
    $ 41.93万
  • 项目类别:
Investigation of Target Protein Degradation and Its Effect on Enhancing Cancer-Specific Antigen Presentation by Quantitative Mass Spectrometry
通过定量质谱研究靶蛋白降解及其对增强癌症特异性抗原呈递的影响
  • 批准号:
    23K04971
  • 财政年份:
    2023
  • 资助金额:
    $ 41.93万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Promoting cancer cells' antigen presentation for serving as better targets for T cell immunotherapy
促进癌细胞的抗原呈递,作为 T 细胞免疫治疗的更好靶点
  • 批准号:
    2885451
  • 财政年份:
    2023
  • 资助金额:
    $ 41.93万
  • 项目类别:
    Studentship
Targeting immunoproteasome-mediated antigen presentation in colorectal cancer immunotherapy
结直肠癌免疫治疗中靶向免疫蛋白酶体介导的抗原呈递
  • 批准号:
    10385926
  • 财政年份:
    2022
  • 资助金额:
    $ 41.93万
  • 项目类别:
Lipid Antigen Presentation as a Driver of T2D Inflammation
脂质抗原呈递作为 T2D 炎症的驱动因素
  • 批准号:
    10509043
  • 财政年份:
    2022
  • 资助金额:
    $ 41.93万
  • 项目类别:
Enhancing antigen presentation in triple negative breast cancers through CD40 agonist, Flt3 ligand, and anthracycline chemotherapy
通过 CD40 激动剂、Flt3 配体和蒽环类化疗增强三阴性乳腺癌的抗原呈递
  • 批准号:
    10704008
  • 财政年份:
    2022
  • 资助金额:
    $ 41.93万
  • 项目类别:
Sex Differences in lipid antigen presentation, impact of lipid antigen presentation on peripheral lipid metabolism
脂质抗原呈递的性别差异,脂质抗原呈递对外周脂质代谢的影响
  • 批准号:
    10818273
  • 财政年份:
    2022
  • 资助金额:
    $ 41.93万
  • 项目类别:
Enhancing antigen presentation in triple negative breast cancers through CD40 agonist, Flt3 ligand, and anthracycline chemotherapy
通过 CD40 激动剂、Flt3 配体和蒽环类化疗增强三阴性乳腺癌的抗原呈递
  • 批准号:
    10349397
  • 财政年份:
    2022
  • 资助金额:
    $ 41.93万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了