T cell regulation by adult prostate stem cells

成体前列腺干细胞对 T 细胞的调节

基本信息

  • 批准号:
    10382302
  • 负责人:
  • 金额:
    $ 18.81万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-04-02 至 2025-03-31
  • 项目状态:
    未结题

项目摘要

Project summary/abstract: Adult prostate stem cells (PSC) are a rare epithelial progenitor population in the prostate. While essential for normal homeostasis, they have also been implicated in hyperplasia and cancer initiation.1-7 Inflammation can fuel hyperplastic diseases through its production of growth factors and cytokines;1, 8, 9 however, the impact of inflammatory factors on PSC and how PSC interact with infiltrating immune cells is not well studied. To examine the cross-talk between epithelial PSC and immune cells, the proposed studies will utilize the Prostate Ovalbumin Expressing Transgenic 3 (POET3), an inducible mouse model of abacterial T cell induced inflammation that produces epithelial and stromal hyperplasia, functioning as a model for human autoimmune prostatitis.10 Current studies in our lab have taken prostates from inflamed and non-inflamed (naïve) POET3 mice, which were harvested, digested, and separated by fluorescence-activated cell sorting (FACS) to isolate an enriched basal PSC population defined as lineage negative (CD45-/CD31-), stem cell antigen-1+, CD49f+ (LSC).11, 12 Single cell mRNA sequencing comparing freshly isolated LSC from naïve (nLSC) and inflamed (iLSC) mice revealed differential expression of multiple immune regulatory genes, suggesting a possible role in regulating T cell response. In vitro suppression assays conducted in our lab confirmed that while neither mature luminal nor nLSC impacted T cell proliferation, iLSC were able to suppress CD8+ T cells. This effect is independent of recognized mechanisms, nitric oxide production, IDO1, or PD-L1.13 Notably, prostates from inflamed mice show a marked enrichment for LSC, suggesting that these cells are protected from T cell attack. Coupled with human BPH data indicating prominent T cell populations enriched for exhaustion and anergy genes, these findings suggest a potential novel mechanism of T cell suppression not previously identified in LSC that is induced under inflammatory conditions, possibly as a tissue protective mechanism. Thus, we hypothesize that adult basal prostate stem cells are able to harness immune regulatory capabilities to suppress T cell function and survive T cell mediated attack. Using the POET3 model of autoimmune inflammation and human BPH samples, studies described herein will explore the T cell suppressive factors utilized by PSC in vitro and evaluate the impact of PSC suppression in vivo. The resulting data will provide a foundation for more thorough study of rare stem/progenitor cells in immune regulation while shedding light on their contribution to epithelial hyperplasia during inflammation.
项目总结/摘要: 成体前列腺干细胞(PSC)是前列腺中罕见的上皮祖细胞群。虽然对于 除了正常的体内平衡外,它们还与增生和癌症的发生有关。 燃料增生性疾病通过其生产的生长因子和细胞因子;1,8,9然而,影响 关于炎症因子对PSC的影响以及PSC如何与浸润性免疫细胞相互作用的研究尚不充分。审查 上皮PSC和免疫细胞之间的串扰,拟议的研究将利用前列腺卵清蛋白 表达转基因3(POET 3),一种无菌T细胞诱导炎症的诱导型小鼠模型, 产生上皮和基质增生,作为人类自身免疫性结肠炎的模型。 我们实验室目前的研究已经从炎症和非炎症(幼稚)POET 3小鼠中取出前列腺, 收获,消化,并通过荧光激活细胞分选(FACS)分离,以分离富集的 基础PSC群体定义为谱系阴性(CD 45-/CD 31-)、干细胞抗原-1+、CD 49 f+(LSC)。11,12 细胞mRNA测序比较了从幼稚(nLSC)和发炎(iLSC)小鼠新鲜分离的LSC, 多个免疫调节基因的差异表达,表明在调节T细胞中可能起作用。 反应在我们实验室进行的体外抑制试验证实,虽然成熟的管腔和nLSC 在受影响的T细胞增殖中,iLSC能够抑制CD 8 + T细胞。这种影响独立于公认的 13值得注意的是,来自发炎小鼠的前列腺显示出显著的炎症机制,一氧化氮产生,IDO 1或PD-L1。 这表明这些细胞被保护免受T细胞攻击。结合人类BPH数据 这些发现表明,显著的T细胞群富含耗竭和无反应性基因, 潜在的新的T细胞抑制机制,以前未在LSC中发现, 炎症状况,可能作为组织保护机制。 因此,我们假设成人基底前列腺干细胞能够利用免疫调节能力, 以抑制T细胞功能并在T细胞介导的攻击中存活。使用POET 3自身免疫模型 在炎症和人BPH样品中,本文所述的研究将探索T细胞抑制因子 通过PSC在体外使用,并评估PSC抑制在体内的影响。 这些数据将为更深入地研究免疫系统中罕见的干/祖细胞提供基础。 调节,同时阐明它们在炎症期间对上皮增生的贡献。

项目成果

期刊论文数量(0)
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Timothy L. Ratliff其他文献

Elevated Cyclic Adenosine 3′, 5′ Monophosphate Enhances Lactic Acid Production by <em>Streptococcus lactis</em>
  • DOI:
    10.3168/jds.s0022-0302(81)82584-2
  • 发表时间:
    1981-03-01
  • 期刊:
  • 影响因子:
  • 作者:
    Timothy L. Ratliff;Dwight E. Talburt
  • 通讯作者:
    Dwight E. Talburt
1861: Involvement of Growth Factors in the Process of Post-Vasectomy Micro-Recanalization
  • DOI:
    10.1016/s0022-5347(18)32034-2
  • 发表时间:
    2007-04-01
  • 期刊:
  • 影响因子:
  • 作者:
    Brandon C. Stahl;Timothy L. Ratliff;Barry R. De Young;Moshe Wald
  • 通讯作者:
    Moshe Wald
Comparison of viral vectors: gene transfer efficiency and tissue specificity in a bladder cancer model.
病毒载体的比较:膀胱癌模型中的基因转移效率和组织特异性。
  • DOI:
  • 发表时间:
    2003
  • 期刊:
  • 影响因子:
    6.6
  • 作者:
    D. Siemens;S. Crist;J. Austin;J. Tartaglia;Timothy L. Ratliff
  • 通讯作者:
    Timothy L. Ratliff
UROLOGICAL SURVEYUro-Science
泌尿科检查Uro-Science
  • DOI:
  • 发表时间:
    2004
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Timothy L. Ratliff
  • 通讯作者:
    Timothy L. Ratliff
Suppressive Effects of Regional Lymph Node Cells and Extracts on Antibody-Dependent Cellular Cytotoxicity
  • DOI:
    10.1016/s0022-5347(17)57501-1
  • 发表时间:
    1978-03-01
  • 期刊:
  • 影响因子:
  • 作者:
    William J. Catalona;Arlene T. Feldman;Timothy L. Ratliff;Robert E. Mccool
  • 通讯作者:
    Robert E. Mccool

Timothy L. Ratliff的其他文献

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{{ truncateString('Timothy L. Ratliff', 18)}}的其他基金

Impact of Inflammation on Adult Prostate Stem Cells
炎症对成体前列腺干细胞的影响
  • 批准号:
    10439754
  • 财政年份:
    2020
  • 资助金额:
    $ 18.81万
  • 项目类别:
Impact of Inflammation on Adult Prostate Stem Cells
炎症对成体前列腺干细胞的影响
  • 批准号:
    10218167
  • 财政年份:
    2020
  • 资助金额:
    $ 18.81万
  • 项目类别:
Impact of Inflammation on Adult Prostate Stem Cells
炎症对成体前列腺干细胞的影响
  • 批准号:
    10655549
  • 财政年份:
    2020
  • 资助金额:
    $ 18.81万
  • 项目类别:
Senior Leadership
高层领导
  • 批准号:
    8681188
  • 财政年份:
    2013
  • 资助金额:
    $ 18.81万
  • 项目类别:
Use of Micro-RNA Arrays to Identify MDSC Functional Pathways and Markers
使用 Micro-RNA 阵列识别 MDSC 功能途径和标记
  • 批准号:
    8451031
  • 财政年份:
    2013
  • 资助金额:
    $ 18.81万
  • 项目类别:
Use of Micro-RNA Arrays to Identify MDSC Functional Pathways and Markers
使用 Micro-RNA 阵列识别 MDSC 功能途径和标记
  • 批准号:
    8601921
  • 财政年份:
    2013
  • 资助金额:
    $ 18.81万
  • 项目类别:
Senior Leadership
高层领导
  • 批准号:
    8470548
  • 财政年份:
    2012
  • 资助金额:
    $ 18.81万
  • 项目类别:
Senior Leadership
高层领导
  • 批准号:
    8182728
  • 财政年份:
    2010
  • 资助金额:
    $ 18.81万
  • 项目类别:
Inflammation and Prostate Cancer Development and Progression
炎症与前列腺癌的发生和进展
  • 批准号:
    8096809
  • 财政年份:
    2010
  • 资助金额:
    $ 18.81万
  • 项目类别:
Inflammation and Prostate Cancer Development and Progression
炎症与前列腺癌的发生和进展
  • 批准号:
    8009233
  • 财政年份:
    2010
  • 资助金额:
    $ 18.81万
  • 项目类别:

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