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; 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.

项目摘要/摘要： 成年前列腺干细胞（PSC）是前列腺中罕见的上皮祖细胞种群。虽然必不可少的 正常的体内稳态，它们在增生和癌症倡议中也暗示。1-7炎症可以 燃料增生性疾病通过其生长因子和细胞因子的产生； 1、8、9，但是， PSC上的炎症因子以及PSC如何与浸润的免疫细胞相互作用并不是很好。检查 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蛋白 表达转基因3（诗3），这是一种绝对T细胞诱导的注射小鼠模型， 产生上皮和基质增生，充当人类自身免疫性前列腺炎的模型。10 我们实验室中目前的研究已从发炎和非炎症（幼稚）诗3小鼠中吸收了前列腺，这些小鼠是 收获，消化并通过荧光激活的细胞分选（FACS）分离以分离富集的 基础PSC种群定义为谱系负（CD45-/CD31-），干细胞抗原-1+，CD49F+（LSC）。11，12单个 比较了来自幼稚（NLSC）和发炎（ILSC）小鼠新鲜分离的LSC的细胞mRNA测序 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 回复。在我们的实验室中进行的体外抑制测定法证实，虽然既没有成熟的腔也不是NLSC 受影响的T细胞增殖，ILSC能够抑制CD8+ T细胞。这种效果独立于公认 机理，一氧化氮的产生，IDO1或PD-L1.13尤其是发炎的小鼠前列腺显示出明显的 LSC的富集，表明这些细胞受到T细胞攻击的保护。与人类BPH数据相结合 这些发现表明突出的T细胞群体富含精疲力尽和厌食基因，这些发现表明 在LSC中未在LSC中鉴定出的T细胞抑制的潜在新型机制 炎症条件，可能是组织保护机制。 这是我们假设成年基础前列腺干细胞能够利用免疫调节能力 抑制T细胞功能并在T细胞介导的攻击中生存。使用自身免疫的Poet3模型 炎症和人类BPH样品，本文所述的研究将探索T细胞抑制因素 由PSC在体外使用，并评估PSC抑制在体内的影响。 最终的数据将为对免疫中的稀有茎/祖细胞进行更彻底的研究为基础 调节，同时阐明了它们对炎症期间对上皮增生的贡献。