CD4 T cells with specificity to noninherited maternal antigen.

CD4 T 细胞对非遗传性母体抗原具有特异性。

基本信息

  • 批准号:
    8790947
  • 负责人:
  • 金额:
    $ 23.4万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-01-20 至 2015-12-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The intermingling and bi-directional transfer of maternal and fetal cells during gestation creates a fascinating and highly relevant physiological model of immune tolerance. Although this interaction has been primarily addressed from the perspective of maternal tolerance to paternal antigens expressed by the fetus, maturing fetal cells also encounter an equally vast array of noninherited maternal antigens that are immunologically foreign. Thus, regulatory pathways are likely in place beginning at the earliest stages of immune cell development to maintain tolerance to noninherited maternal antigen (NIMA). Furthermore, these tolerance pathways are also likely to be maintained long term given the increasingly appreciated sustained microchimerism of maternal cells in offspring. In this regard, there is already compelling evidence illustrating immune recognition and tolerance to NIMA and other foreign antigens with exposure beginning in utero. However, what remains unknown are the immune cell and molecular pathways whereby tolerance to NIMA and other in utero exposed antigens is achieved. We propose key scientific bottlenecks include the inability to precisely identify NIMA responsive immune cells essential for characterizing their molecular phenotype, and the tools for discriminating these potentially rare cells in an antigen specific fashion from those with irrelevant specificity. We show in initial proof of concept feasibility studies these limitations are overcome using transgenic female mice engineered to constitutively and ubiquitously express defined model antigens for mating with non transgenic males that transforms model antigens into surrogate NIMA. In turn, newly developed tetramer staining and enrichment techniques allow endogenous immune cells with surrogate NIMA specificity to be tracked in an antigen specific fashion. Using this approach, our initial findings show CD4 T cells with NIMA specificity are (i) found in the peripheral lymphoid tissue in adult mice, (ii) selectively enriched for Foxp3 expression with >2-fold higher levels compared with naive or noninherited paternal antigen exposed controls, and (iii) expand only modestly while retaining exaggerated Foxp3 expression after infection with recombinant Listeria monocytogenes engineered to express the same NIMA associated peptide as a pathogen associated antigen. Based on these initial findings, our overall hypothesis is physiological exposure to noninherited maternal antigen in utero triggers tolerance through the selective accumulation of suppressive Foxp3+ regulatory T cells with specificity to these immunologically foreign antigens. To investigate this hypothesis, two inter-related aims are proposed to establish the precise immune cell subset that dictates NIMA induced tolerance, and define the necessity for maternal cell microchimerism in tolerance phenotypes for CD4 T cells with NIMA specificity. The successful completion of the aims for this exploratory grant will unlock and establish the scientific framework for additional more in depth functional and mechanistic studies aimed at further unraveling this under appreciated aspect of immunological tolerance.
描述(由申请人提供):妊娠期间母体和胎儿细胞的混合和双向转移创建了一个引人入胜和高度相关的免疫耐受生理模型。虽然这种相互作用主要是从母体对胎儿表达的父系抗原的耐受性的角度来解决的,但成熟的胎儿细胞也会遇到同样大量的非遗传母体抗原,这些抗原在免疫上是外来的。因此,在免疫细胞发育的最早阶段就可能存在调节通路,以维持对非遗传性母体抗原(NIMA)的耐受性。此外,考虑到母体细胞在子代中持续的微嵌合现象日益受到重视,这些耐受途径也可能长期保持。在这方面,已经有令人信服的证据表明,从子宫开始接触NIMA和其他外国抗原的免疫识别和耐受性。然而,目前尚不清楚的是免疫细胞和分子途径,通过这些途径可以实现对NIMA和其他宫内暴露抗原的耐受。我们提出的关键科学瓶颈包括无法准确识别NIMA反应免疫细胞,这些细胞是表征其分子表型所必需的,以及以抗原特异性方式区分这些潜在稀有细胞和那些无关特异性的工具。我们在最初的概念论证可行性研究中表明,使用转基因雌性小鼠克服了这些限制,转基因雌性小鼠被设计为结构性地和普遍地表达特定的模型抗原,用于与非转基因雄性交配,将模型抗原转换为代理NIMA。反过来,新开发的四聚体染色和浓缩技术允许以抗原特异的方式跟踪具有替代NIMA特异性的内源性免疫细胞。使用这种方法,我们的初步发现 结果表明,具有NIMA特异性的CD4T细胞(I)在成年小鼠的外周淋巴组织中被发现,(Ii)选择性地富含Foxp3表达,与幼稚或非遗传的父系抗原暴露的对照组相比,水平高2倍,(Iii)在感染重组单核细胞增生性李斯特菌后仅适度扩张,同时保留夸大的Foxp3表达,重组单核细胞增生性李斯特菌经改造后表达与病原体相关抗原相同的NimA相关多肽。基于这些初步发现,我们的总体假设是,在子宫内生理性地暴露于非遗传性母体抗原,通过选择性积累针对这些免疫外来抗原的抑制性Foxp3+调节性T细胞来触发耐受。为了研究这一假说,提出了两个相互关联的目标:建立精确的免疫细胞亚群,以决定NIMA诱导的耐受;以及确定具有NIMA特异性的CD4T细胞耐受表型中母体细胞微嵌合的必要性。这项探索性拨款的目标的成功完成将为更多更深入的功能和机制研究奠定科学框架,旨在进一步揭开免疫耐受性这一被忽视的方面的面纱。

项目成果

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{{ truncateString('Sing Sing Way', 18)}}的其他基金

Kruppel-like factor-2 CD4+ T cells and intestinal inflammation
Kruppel 样因子 2 CD4 T 细胞和肠道炎症
  • 批准号:
    10730990
  • 财政年份:
    2023
  • 资助金额:
    $ 23.4万
  • 项目类别:
Progesterone induced immune modulation during pregnancy – supplemental research in COVID-19
怀孕期间黄体酮诱导的免疫调节 — COVID-19 的补充研究
  • 批准号:
    10200397
  • 财政年份:
    2021
  • 资助金额:
    $ 23.4万
  • 项目类别:
Progesterone induced immune modulation during pregnancy
怀孕期间黄体酮诱导的免疫调节
  • 批准号:
    9797361
  • 财政年份:
    2019
  • 资助金额:
    $ 23.4万
  • 项目类别:
Progesterone induced immune modulation during pregnancy
怀孕期间黄体酮诱导的免疫调节
  • 批准号:
    10625933
  • 财政年份:
    2019
  • 资助金额:
    $ 23.4万
  • 项目类别:
Progesterone induced immune modulation during pregnancy
怀孕期间黄体酮诱导的免疫调节
  • 批准号:
    10441395
  • 财政年份:
    2019
  • 资助金额:
    $ 23.4万
  • 项目类别:
Progesterone induced immune modulation during pregnancy
怀孕期间黄体酮诱导的免疫调节
  • 批准号:
    10192641
  • 财政年份:
    2019
  • 资助金额:
    $ 23.4万
  • 项目类别:
Progesterone induced immune modulation during pregnancy
怀孕期间黄体酮诱导的免疫调节
  • 批准号:
    10653014
  • 财政年份:
    2019
  • 资助金额:
    $ 23.4万
  • 项目类别:
Progesterone induced immune modulation during pregnancy – supplemental research in COVID-19
怀孕期间黄体酮诱导的免疫调节 — COVID-19 的补充研究
  • 批准号:
    10344851
  • 财政年份:
    2019
  • 资助金额:
    $ 23.4万
  • 项目类别:
Systemic immune modulation by enteric commensal fungi
肠道共生真菌的系统免疫调节
  • 批准号:
    9066379
  • 财政年份:
    2016
  • 资助金额:
    $ 23.4万
  • 项目类别:
Immunological identity redefined by genetically foreign microchimeric cells
外源微嵌合细胞重新定义免疫学特性
  • 批准号:
    9339521
  • 财政年份:
    2016
  • 资助金额:
    $ 23.4万
  • 项目类别:

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