The human memory T cell compartment changes across tisses of the female reproductive tract
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE163260 | GEO | 2021/04/28
REPOSITORIES: GEO
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Project description:Memory CD4 T cells in tissues fulfill numerous functions that are critical for local immune homeostasis and protection against pathogens. Previous studies have highlighted the phenotypic and functional heterogeneity of circulating and tissue-resident memory CD4 T cells across different human tissues such as skin, lung, liver, and colon. Comparatively little is known in regard to memory CD4 T cells across tissues of the female reproductive tract (FRT). We examined CD4 T cells in donor-matched vaginal, ecto- and endocervical tissues, which differ in mucosal structure and exposure to external environmental stimuli. We hypothesized that this could be reflected by tissue-specific differences in the memory CD4 T cell compartment. We found differences in CD4 subset distribution across these tissues. Specifically, CD69+CD103+ CD4 T cells were significantly more abundant in vaginal than cervical tissues. In contrast, the transcriptional profiles of CD4 subsets were fairly conserved across FRT tissues. CD69+CD103+ CD4 T cells showed a TH17 bias independent of tissue niche. Our data suggest that FRT tissues affect T cell subset distribution but have limited effects on the transcriptome of each subset. We discuss the implications for barrier immunity in the FRT.
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Project description:Mitogen-activated protein 3 kinase 1 (MAP3K1) has a plethora of cell type-specific functions not yet fully understood. Herein, we describe a role for MAP3K1 in female reproductive tract (FRT) development. MAP3K1 kinase domain-deficient female mice exhibited an imperforate vagina, labor failure and infertility. These defects corresponded with shunted Müllerian ducts (MDs), the embryonic precursors of FRT, that manifested as a contorted caudal vagina and abrogated vaginal-urogenital sinus fusion in neonates. The MAP3K1 kinase domain is required for optimal activation of the Jun-N-terminal kinase (JNK) and cell polarity in the MD epithelium, and for upregulation of WNT signaling in the mesenchyme surrounding the caudal MD. The MAP3K1-deficient epithelial cells and MD epithelium had reduced expression of WNT7B ligands. Correspondingly, conditioned media derived from MAP3K1-competent, but not -deficient, epithelial cells activated a TCF/Lef-luciferase reporter in fibroblasts. These observations indicate that MAP3K1 regulates MD caudal elongation and FRT development, in part through the induction of paracrine factors in the epithelium that trans-activate WNT signaling in the mesenchyme.
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Project description:The aim of the study was to assess the cellular composition and transcriptional changes at single-cell resolution of the female reproductive tract across the four stages of estrus cycle in young adult mice (ovary, oviduct, uterus, cervix and vagina, with spleen as a comparison) and compared this with similar analyses of decidualization (uterus) and ageing (ovary, oviduct, uterus, cervix, vagina and spleen). Vaginal smears were used to stage the estrus cycle in young mice. To collect the decidualized uteri mice were mated and uterine tissue was collected from pregnant mice at day 5.5 after mating. Tissues of aged mice were collected at the age of 18 months. All tissues were collected and digested using a collagenase and trypsin protocol to obtain single cell suspension. Libraries were prepared using the 10x scRNA-seq protocol.
2023-02-01 | E-MTAB-11491 | biostudies-arrayexpress
Project description:Intravaginal HIV microbicides could provide women with a self-controlled means for HIV prevention, but results from clinical trials have been largely disappointing. We postulated that unrecognized effects of intravaginal gels on the upper female reproductive tract (FRT) might contribute to the lower-than-expected efficacy of HIV microbicides. In this observational crossover study, 28 healthy female volunteers used no product (control cycle) or used a nightly application of intravaginal nonoxynol-9 gel [N9] as a 'failed' microbicide or the universal placebo gel [UPG] as a 'safe' gel, from the end of menses to the mid-luteal phase (intervention cycles). They then underwent sample collection for measurements of T-cell phenotypes, transcriptional profiling, and protein levels from 3 anatomic sites above the vagina: the cervical transformation zone, the endocervix and the endometrium. We used hierarchical statistical models to estimate mean (95% CI) intervention:control fold-changes in relevant phenotype levels. Exposure to N9 and UPG generated a common 'harm signature' that included transcriptional up-regulation of inflammatory genes CCL20 and IL8 in the cervix, decreased protein concentrations of secretory leukocyte protease inhibitor and increased percentages of terminally differentiated CD4+ effector T-cells in the endocervix, and transcriptional up-regulation of inflammatory mediators KIR3DS1, glycodelin-A, and osteopontin in the endometrium. These results underscore the need to consider the effects of microbicide agents and gel excipients on the upper FRT in studies of vaginal microbicides. Given the pro-inflammatory effects of UPG on the upper FRT, it may not be a suitable placebo for microbicide trials. Upper tract effects of intravaginal gels in women. This is a cross sectional study involving control samples versus treatment for two tissue types.
2015-08-10 | E-GEOD-58090 | biostudies-arrayexpress
Project description:The human memory T cell compartment changes across tisses of the female reproductive tract
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Project description:Highly Exposed-Seronegatives (HESN) individuals do not contract HIV-1 infection despite long-term exposure; few comprehensive studies examining behavior, mucosal tissue, and peripheral immune parameters in sexually-exposed HESN have been completed. To this end, we assessed rate of condomless vaginal sex, the immune activation status (peripheral blood) and gene expression (ectocervical biopsies) in female cohort of high-risk female sex workers [FSW] (n=50) and non-sex worker women [CG] (n=32) in San Juan, Puerto Rico, USA. Of the 50 FSWs examined only 5 had detectable anti-HIV responses by either HIV gag-specific CD8+ T-Cell responses or mucosal anti-HIV envelope IgG/IgA. FSW had a uniform lower CD38 expression on circulating CD4+ or CD8+ T-Cells (both: p<0.0001:Wilcoxon Rank Sum). Cervical tissue from FSWs had greater levels of CD4+ T-Cell (p=0.040), CD123+ plasmacytoid Dendritic Cells (p=0.013) and CD68+ macrophage infiltrates (p=0.038). Cervical gene expression by RNA microarray indicated that FSW had a gene signature characterized by lower expression of genes associated with leukocyte homing and chemotaxis; partial interferon regulated gene signature; and lower gene expression of genes required for HIV infection such as CD4 and NUP153 indicating a lower mucosal immune activation state and reduced susceptibility to HIV-1 infection within mucosal tissue. Notably, Interferon (IFN)-ε expression was higher in FSW than CG women, as detected by RNA (microarray) and protein (IHC) expression in cervical epithelium. The observed levels of IFNε were associated with the reported frequency of unprotected intercourse. Finally, IFNε was induced by treatment of the ECT1 cell line with seminal fluid, suggesting that semen exposure may contribute to long-term protection. Decreased levels of immune activation and gene expression required for HIV infection along with semen-induced epithelial Interferon ε production within the reproductive tract of FSWs highlight distinct host intrinsic resistance mechanisms that may contribute to long-term HIV seronegative status in spite of high-risk condomless sex.
2019-11-21 | GSE63441 | GEO
Project description: Not available
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Project description:HIV-1 sexual transmission occurs mainly via mucosal semen exposures. In the female reproductive tract (FRT), seminal plasma (SP) induces physiological modifications, including inflammation. An effective HIV-1 vaccine should elicit mucosal immunity. However, modifications of vaccine responses by the local environment remain to be characterized. Using a modified vaccinia virus Ankara (MVA) as a vaccine model, we characterized the impact of HIV-1+ SP intravaginal exposure on the local immune responses of nonhuman primates. Multiple HIV-1+ SP exposures did not impact the anti-MVA antibody responses. However, SP exposures revealed an anti-MVA responses mediated by CD4+ T cells, which was not observed in the control group. Multi-parameter approaches clearly identified the cervix as the most impacted compartment in the FRT. The frequency and the quality of specific anti-MVA CD8+ T cell responses increased in the FRT exposed to SP. Furthermore SP exposures induced a local cell recruitment of antigen presenting cells, especially CD11c+ cells and CD8+ T cell recruitment in the FRT draining lymph nodes. CD11c+ cell recruitment was associated with upregulation of inflammation-related gene expression after SP exposures in the cervix. We thus highlight the fact that physiological conditions, such as SP exposures, should be taken into consideration to test and to improve vaccine efficacy against HIV-1 and other sexually transmitted infections.
2019-02-12 | E-MTAB-7639 | biostudies-arrayexpress
Project description:Human ectocervical and endocervical cells immortalized by HPV16 E6/E7 (designated as Ect and End, respectively) and normal human immortalized keratinocytes (NIKS), were transfected with whole genomes of HPV16 or HPV18, and were subsequently grown in standard monolayer culture until passage 2. Total RNAs were extracted and subjected to TORAY 3D-gene analysis service using the 3D-Gene Human Oligo chip 25K (TORAY, Tokyo, Japan).
2019-08-01 | GSE131076 | GEO