T cell regulation by adult prostate stem cells

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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.