The transcription factor NFκB has been associated with the timing of menopause in a large human genome-wide association study. Furthermore, preclinical studies demonstrate that loss of Tumor necrosis factor alpha (Tnfα) or its receptor Tnfr2 slows primordial follicle growth activation (PFGA). Although Tnfα:receptor signaling stimulates NFκB and may mechanistically link these findings, very little is known about NFκB signaling in PFGA. Because signaling downstream of Tnfα/Tnfr2 ligand/receptor interaction has not been interrogated as relates to PFGA, we evaluated the expression of key NFκB signaling proteins in primordial and growing follicles, as well as during ovarian aging. We show that key members of the NFκB pathway, including subunits, activating kinases and inhibitory proteins, are expressed in the murine ovary. Furthermore, the subunits p65 and p50, and the cytosolic inhibitory proteins IκBα and IκBβ, are present in ovarian follicles, including at the primordial stage. Finally, we assessed PFGA in genetically modified mice (AKBI) previously demonstrated to be resistant to inflammatory stress-induced NFκB activation due to overexpression of the NFκB inhibitory protein IκBβ. Consistent with the hypothesis that NFκB plays a key role in PFGA, AKBI mice exhibit slower PGFA than wild-type (WT) controls, and their ovaries contain nearly twice the number of primordial follicles as WT
Problem: Immune cell trafficking and surveillance within the ovary and fallopian tube are thought to impact fertility and also tumorigenesis in those organs. However, little is known of how native cells of the ovary and fallopian tube interact with resident immune cells. Interaction of the Programmed Cell Death Protein-1 (PD-1/PDCD-1/CD279) checkpoint with PD-L1 is associated with downregulated immune response.We have begun to address the question of whether PD-1 ligand or its receptors (PD-L1/-L2) can regulate immune cell function in these tissues of the female reproductive tract.Method of study: PD-1 and ligand protein expression was evaluated in human ovary and fallopian tube specimens, the latter of which included stages of tubal cell transformation and early tumorigenesis. Ovarian expression analysis included the determination of the proteins in human follicular fluid (HFF) specimens collected during in vitro fertilization procedures. Finally, checkpoint bioactivity of HFF was determined by treatment of separately-isolated human T cells and the measurement of interferon gamma (IFN𝛾).
16The Programmed Cell Death Protein-1 (PD-1/PDCD-1/CD279) checkpoint has powerful immunomod-17 ulatory action, including in the context of cancer. PD-1 receptor activation by its ligands (PD-18 L1/2) is associated with downregulated immune response, and tumor cells can avoid surveillance 19 via PD-1 and/or ligand expression. While receptor expression is largely limited to lymphoid, 20 myeloid, and tumor cells, we show that membrane bound and soluble variants of PD-1 and lig-21 ands are also expressed by permanent constituent cell types of the human ovary and fallopian 22 tube, including granulosa cells and oocytes. PD-1 and soluble ligands were highly enriched in ex-23 osome fractions in human follicular fluid at bioactive levels that can control T cell PD-1 activation. 24 PD-1 checkpoint signaling may be involved in physiological ovarian functions including follicle, 25 and ultimately, germline and embryo immune-privilege. 26PD-1.28 54 cells [29][30][31][32][33][34][35] . Early transformation events can result in serous tubal intraepithelial lesions (STILs), 55 which are characterized by a "p53 signature" in morphologically unremarkable FTE cells, visi-56 ble on immunohistochemical staining as overexpression in 12 or more consecutive non-ciliated 57 cells. Mutations in the tumor suppressor can result in either nuclear stabilization of the mutant 58 p53 variant, or, in loss of p53 expression 36 . STILs can then progress to another stereotypical stage, 59 the serous tubal intraepithelial carcinoma (STIC) 30,37,38 . STIC cells detach from the tubal lumen 60 and engraft at distant sites within the peritoneum, including the surface of the ovary at ovulation 61 site(s) 39,40 . 62During a preliminary evaluation of Pd-1 pathway protein expression in immune cells within 63 the mouse ovary, we detected broad expression of the receptor and ligands in the organ, in both 64 somatic cells and oocytes. There was also an existing report in a publicly-available large-scale 65 gene expression screen (LifeMap Discovery R ) that showed that PD-1 pathway transcripts are de-66 tectable in human cumulus granulosa cells (HCGC). Because of potential relevance of these initial 67 data to ovarian function and ovarian cancer development, a more extensive analysis of the PD-1 68 checkpoint in the human ovary and fallopian tube was warranted. We tested whether the PD-1 69 checkpoint acts within the human ovary and fallopian tube in ways suggestive of physiological 70 function, including testing whether soluble PD-1 or ligand proteins are present in human follicular 71 fluid (HFF) at levels capable of regulating immune function. 72 Results 73In an immunohistochemical study of both pre-and postmenopausal human ovarian tissue ( Fig. 74 1), we found that PD-1, PD-L1, and PD-L2 are are widely expressed, and this was conserved in the 75 mouse ovary ( Fig. S1, human tonsil positive controls shown in Fig. S2). In human premenopausal 76 specimens (n=8 unique patient samples evaluated), PD-1 was detectable in the oocytes of non-77 growing (i...
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