T cell regulation by adult prostate stem cells

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。

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.