Molecular regulation of uterine leukocyte recruitment during early pregnancy in the mouse

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297

312

In mice, seminal fluid elicits an inflammation-like response in the female genital tract that activates immune adaptations to advance the likelihood of conception and pregnancy. In this study, we examined whether similar changes in leukocyte and cytokine parameters occur in the human cervix in response to the male partner’s seminal fluid. After a period of abstinence in proven-fertile women, duplicate sets of biopsies were taken from the ectocervix in the periovulatory period and again 48 h later, 12 h after unprotected vaginal coitus, vaginal coitus with use of a condom, or no coitus. A substantial influx of CD45+ cells mainly comprising CD14+ macrophages and CD1a+ dendritic cells expressing CD11a and MHC class II was evident in both the stratified epithelium and deeper stromal tissue after coitus. CD3+CD8+CD45RO+ T cells were also abundant and increased after coitus. Leukocyte recruitment did not occur without coitus or with condom-protected coitus. An accompanying increase in CSF2, IL6, IL8, and IL1A expression was detected by quantitative RT-PCR, and microarray analysis showed genes linked with inflammation, immune response, and related pathways are induced by seminal fluid in cervical tissues. We conclude that seminal fluid introduced at intercourse elicits expression of proinflammatory cytokines and chemokines, and a robust recruitment of macrophages, dendritic cells, and memory T cells. The leukocyte and cytokine environment induced in the cervix by seminal fluid appears competent to initiate adaptations in the female immune response that promote fertility. This response is also relevant to transmission of sexually transmitted pathogens and potentially, susceptibility to cervical metaplasia.

Section: Discussionsupporting

confidence: 85%

Seminal Fluid Induces Leukocyte Recruitment and Cytokine and Chemokine mRNA Expression in the Human Cervix after Coitus

Sharkey

Tremellen

Jasper

et al. 2012

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297

312

“…This accords with our previous observations on the T cell response to mating (28) and reflects that OVA Ag mainly originates within the accessory gland secretions, not the testes, because OVA levels were comparable in ejaculates from vasectomized and intact males. T cell activation would be facilitated by proinflammatory signals in seminal plasma that activate cytokine and chemokine expression (65), leading to recruitment and activation of macrophages and DCs in the uterine endometrial tissue (66 (68,69). Superovulation profoundly alters expression of uterine GM-CSF, LIF, and other cytokines known to influence APC function, and changes the abundance and phenotypes of macrophage and DC populations (70, 71) (S. Robertson, unpublished observations).…”

Section: Discussionmentioning

confidence: 99%

Cross-Presentation of Male Seminal Fluid Antigens Elicits T Cell Activation to Initiate the Female Immune Response to Pregnancy

Moldenhauer

Diener

Thring

et al. 2009

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204

212

The events that generate T cell-mediated immune tolerance in early pregnancy are ill-defined. To investigate the significance of seminal fluid Ags in activating maternal T cells, and define the underlying Ag presentation pathways, OVA-specific T cells were adoptively transferred to female mice inseminated by males ubiquitously expressing membrane-bound OVA. OVA-reactive CD8+ OT-I and CD4+ OT-II T cells transferred to mated recipients expressed activation markers CD25 and CD69 and proliferated vigorously in the para-aortic lymph nodes, but not in distal lymph nodes or spleen, and OT-I T cells expressed IFN-γ and IL-2. In contrast, OT-I T cells transferred later in pregnancy or up to 10 days postpartum expressed CD25 and CD69 and proliferated in all peripheral lymphoid tissues examined. OVA Ag was present predominantly in the plasma fraction of seminal fluid, and seminal plasma, but not sperm, was necessary for T cell proliferation. Female H-2Kb bone marrow-derived cells expressing TAP were essential for OT-I T cell proliferation, but responses were not elicited by OVA Ag presented by paternal MHC in seminal fluid or associated with placental cells. This study shows that at conception, seminal fluid drives activation and expansion of paternal Ag-reactive CD4+ and CD8+ T cell populations, and female APCs have an essential role in cross-presenting Ag to CD8+ T cells via a TAP-dependent pathway. Delivery of paternal Ags and immune-deviating cytokines by seminal fluid at conception may activate Ag-dependent CD4+ and CD8+ regulatory T cells mediating tolerance of pregnancy.

“…Their altered phenotype in the absence of GM-CSF could be expected to compromise DC function during the postimplantation period when DCs begin to process Ags released by invading placental trophoblasts (32,33) and have an essential role in regulating the vascular changes that ensure an adequate decidual response and placental cell invasion (2,46). The presence of otherwise normal numbers of DCs and macrophages in the GM-CSF-deficient uterus during early pregnancy is explained by the array of other chemokines and cytokines expressed in the uterus, including CSF1, RANTES, MIP1a, MIP1b, and MCP1 (47)(48)(49). These data are consistent with studies in other tissues of Csf2 2/2 mice showing that in steady-state conditions, the numbers of myeloid and DC cell populations in LNs and peripheral organs are essentially normal (27,50).…”

Section: Discussionmentioning

confidence: 99%

GM-CSF Is an Essential Regulator of T Cell Activation Competence in Uterine Dendritic Cells during Early Pregnancy in Mice

Moldenhauer

Keenihan

Hayball

et al. 2010

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Uterine dendritic cells (DCs) are critical for activating the T cell response mediating maternal immune tolerance of the semiallogeneicfetus. GM-CSF (CSF2), a known regulator of DCs, is synthesized by uterine epithelial cells during induction of tolerance in early pregnancy. To investigate the role of GM-CSF in regulating uterine DCs and macrophages, Csf2-null mutant and wild-type mice were evaluated at estrus, and in the periconceptual and peri-implantation periods. Immunohistochemistry showed no effect of GM-CSF deficiency on numbers of uterine CD11c+ cells and F4/80+ macrophages at estrus or on days 0.5 and 3.5 postcoitum, but MHC class II+ and class A scavenger receptor+ cells were fewer. Flow cytometry revealed reduced CD80 and CD86 expression by uterine CD11c+ cells and reduced MHC class II in both CD11c+ and F4/80+ cells from GM-CSF–deficient mice. CD80 and CD86 were induced in Csf2−/− uterine CD11c+ cells by culture with GM-CSF. Substantially reduced ability to activate both CD4+ and CD8+ T cells in vivo was evident after delivery of OVA Ag by mating with Act-mOVA males or transcervical administration of OVA peptides. This study shows that GM-CSF regulates the efficiency with which uterine DCs and macrophages activate T cells, and it is essential for optimal MHC class II- and class I-mediated indirect presentation of reproductive Ags. Insufficient GM-CSF may impair generation of T cell-mediated immune tolerance at the outset of pregnancy and may contribute to the altered DC profile and dysregulated T cell tolerance evident in infertility, miscarriage, and preeclampsia.