T cell regulation by adult prostate stem cells

成体前列腺干细胞对 T 细胞的调节

• 批准号: 10382302
• 负责人: Timothy L. Ratliff
• 金额: $ 18.81万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10382302
• 关键词: 5 Alpha-Reductase Inhibitor; Address; Adrenergic alpha-Antagonists; Adult; Affect; Age; Antigens; Apoptosis; Autoimmune; Basal Cell; Behavior; Benign Prostatic Hypertrophy; Biological Assay; Biological Process; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell physiology; Cells; Chronic; Coupled; Data; Development; Disease; Epithelial; Evaluation; Exhibits; Fluorescence-Activated Cell Sorting; Foundations; Frequencies; Functional disorder; Genes; Granzyme; Growth Factor; Harvest; Homeostasis; Human; Hyperplasia; Immune; Immune Targeting; Immunologic Suppressor Factors; In Vitro; Incidence; Incontinence; Inflammation; Inflammatory; Investigation; Light; Mediating; Mesenchymal Stem Cells; Modeling; Mus; Myeloid-derived suppressor cells; Nitric Oxide; Nocturia; Nodule; Operative Surgical Procedures; Ovalbumin; PECAM1 gene; PTPRC gene; Pathologic; Pathway interactions; Patients; Play; Population; Prevalence; Production; Proliferating; Prostate; Prostatic Diseases; Prostatic hypertrophy; Quality of life; Regulator Genes; Resistance; Role; Sampling; Sampling Studies; Stromal Hyperplasia; T cell anergy; T cell regulation; T cell response; T-Cell Proliferation; T-Lymphocyte; Tissues; Transgenic Organisms; Tumor-infiltrating immune cells; Urethra; anergy; autoimmune inflammation; cancer initiation; cell killing; cytokine; differential expression; disabling symptom; epithelial stem cell; exhaustion; experimental study; immunoregulation; improved; in vivo; inflammatory milieu; male health; men; micturition urgency; mouse model; novel; progenitor; programmed cell death ligand 1; prostatitis; single cell mRNA sequencing; single-cell RNA sequencing; stem; stem cell population; stem cells; targeted treatment

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.

项目概要/摘要： 成体干细胞 (PSC) 是前列腺中罕见的上皮祖细胞群，同时也是前列腺所必需的。 正常的体内平衡，它们也与增生和癌症发生有关。1-7 炎症可以 通过产生生长因子和细胞因子加剧增生性疾病；1, 8, 9 然而， PSC 上的炎症因子以及 PSC 如何与浸润性免疫细胞相互作用尚未得到充分研究。 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 (POET3)，一种非细菌 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前列腺炎的模型。 10 我们实验室目前的研究已经从发炎和非发炎（幼稚）POET3 小鼠身上采集了前列腺， 收获、消化并通过荧光激活细胞分选 (FACS) 分离，以分离出富集的 PSC 群体定义为谱系阴性 (CD45-/CD31-)、干细胞抗原 1+、CD49f+ (LSC)。11、12 单 细胞 mRNA 测序比较了来自幼稚 (nLSC) 和炎症 (iLSC) 小鼠的新鲜分离的 LSC 多个免疫调节基因的差异表达，表明可能在调节 T 细胞中发挥作用 我们实验室进行的体外抑制试验证实了这一点，而成熟的 luminal 和 nLSC 都没有。 影响 T 细胞增殖，iLSC 能够抑制 CD8+ T 细胞，这种作用与公认的无关。 机制、一氧化氮产生、IDO1 或 PD-L1.13 值得注意的是，发炎小鼠的前列腺显示出明显的 结合人类 BPH 数据，表明这些细胞免受 T 细胞攻击。 表明显着的 T 细胞群富含疲劳和无反应基因，这些发现表明 之前在 LSC 中未发现的 T 细胞抑制的潜在新机制，该机制是在以下条件下诱导的 炎症状况，可能作为一种组织保护机制。 因此，我们追求成人基底前列腺干细胞能够利用免疫调节能力 使用 POET3 自身免疫模型抑制 T 细胞功能并在 T 细胞介导的攻击中存活。 炎症和人类 BPH 样本，本文描述的研究将探索 T 细胞抑制因子 PSC 体外利用并评估体内 PSC 抑制的影响。 由此产生的数据将为更深入地研究免疫中稀有干/祖细胞提供基础 调节，同时揭示它们在炎症过程中对上皮增生的贡献。