Control of Uterine Microenvironment by Foxp3+ Cells Facilitates Embryo Implantation

Abstract

Implantation of the fertilized egg into the maternal uterus depends on the fine balance between inflammatory and anti-inflammatory processes. Whilst regulatory T cells (Tregs) are reportedly involved in protection of allogeneic fetuses against rejection by the maternal immune system, their role for pregnancy to establish, e.g., blastocyst implantation, is not clear. By using 2-photon imaging we show that Foxp3+ cells accumulated in the mouse uterus during the receptive phase of the estrus cycle. Seminal fluid further fostered Treg expansion. Depletion of Tregs in two Foxp3.DTR-based models prior to pairing drastically impaired implantation and resulted in infiltration of activated T effector cells as well as in uterine inflammation and fibrosis in both allogeneic and syngeneic mating combinations. Genetic deletion of the homing receptor CCR7 interfered with accumulation of Tregs in the uterus and implantation indicating that homing of Tregs to the uterus was mediated by CCR7. Our results demonstrate that Tregs play a critical role in embryo implantation by preventing the development of a hostile uterine microenvironment.

T cell behavior at the maternal-fetal interface

“…This idea has been gaining support from multiple studies in mice showing that T Reg cell deficiency in the peri-implantation period, induced experimentally via a variety of means, causes either implantation failure or embryo resorption soon after implantation. In some studies (Aluvihare et al , 2004, Shima et al , 2010) but not others (Teles et al , 2013a), this failure occurs in allogeneic but not syngeneic mating combinations, suggesting that T cell responses to alloantigens present in semen might be important for implantation. Consistent with this possibility, maternal CD8 T cells undergo a transient wave of proliferation in the uterine LN following copulation in response to a surrogate seminal antigen (Moldenhauer et al , 2009).…”

Decoding the chemokine network that links leukocytes with decidual cells and the trophoblast during early implantation

“…71 During the implantation period, CCL5 produced by human endometrium it has the potential to act in an autocrine manner by the differential expression of its receptors CCR1, CCR3, and CCR5. 85,86 CCL5 also is produced by human endometrial T-infiltrated lymphocytes, CD4C and CD8C, which production increased in the presence of physiological P4 concentrations. 85 At later pregnancy stages, the Foxp3C cell subset suffer an expansion and using a Rag-1 ¡/¡ model of cell transfer Tregs, Teles et al demonstrated that natural Tregs (thymic origin), are needed for pregnancy establishment and induced Tregs (iTregs) contributes to the Treg pool in the periphery.…”

“…85,86 CCL5 also is produced by human endometrial T-infiltrated lymphocytes, CD4C and CD8C, which production increased in the presence of physiological P4 concentrations. 85 At later pregnancy stages, the Foxp3C cell subset suffer an expansion and using a Rag-1 ¡/¡ model of cell transfer Tregs, Teles et al demonstrated that natural Tregs (thymic origin), are needed for pregnancy establishment and induced Tregs (iTregs) contributes to the Treg pool in the periphery. 90 Trophoblast cells not only contribute to iTreg cell differentiation, but also selectively recruit them.…”

In vivo visualization of uterine mast cells by two-photon microscopy

“…The application of two-photon microscopy to transgenic mouse models increases exponentially (Zipfel et al 2003). Of interest for the reproduction field, it has been recently reported that this methodology can be used for the tracking of dendritic cells (DCs; Zenclussen et al 2013) and regulatory T cells (Treg; Teles et al 2013) as well as for the imaging of the mouse placenta under physiological (Zenclussen et al 2012) Figure 4 Intravital two-photon microscopy allows the quantification of uterine MCs (uMCs) in virgin and pregnant uteri of C57BL/6J-Mcpt5-Cre ROSA26-EYFP mice. The number of MCs was determined in representative z-stacks of virgin or pregnant female C57BL/6J-Mcpt5-Cre ROSA26-EYFP mice (nZ5/cycle in non-pregnant and nZ3/stage in pregnant mice) using Zeiss LSM Image Browser software.…”

“…Not only do they contribute to innate and adaptive immune responses (Galli et al 2005, St John & Abraham 2013, but also they are directly involved in non-immunological processes including tissue remodeling and angiogenesis (Varayoud et al 2004, Bosquiazzo et al 2007, Theoharides et al 2010. Their effects are mainly mediated by granule-stored mediators such as metalloproteases, MC-specific proteases, tissue plasminogen activator (tPA), vascular endothelial growth factor (VEGF), transforming growth factor b (TGFb) (Galli et al 2005) and galectin 1 (Gal1, Woidacki et al 2013) that are released upon activation.…”