Significance: Early-life immune responses have been described as suboptimal, with neonates and infants being susceptible to infections. Vγ9Vδ2 T cells are the first T lymphocytes to be generated in the human fetus. Their T cell receptor-mediated responses to in vitro stimulation and their effector functions at birth are weaker compared with those in adults, possibly reflecting the need for tolerance in utero. However, here we show that upon transition to the prominent microbial exposure early after birth, public fetal-derived Vγ9Vδ2 T cells expand and differentiate into potent cytotoxic effector cells. Thus, they provide newborns with a first line of antimicrobial effector T cells in order to combat infections in early life.

Pregnancy is a state where high and stage-dependent plasticity of the maternal immune system is necessary in order to equilibrate between immunosuppression of harmful responses towards the fetus and ability to fight infections. TCR γδ cells have been implicated in the responses in infectious diseases, in the regulation of immune responses, and in tissue homeostasis and repair. The variety of functions makes γδ T cells a particularly interesting population during pregnancy. In this study, we investigated the proportion, phenotype and TCR γ and δ repertoires of γδ T cells at the maternal–fetal interface and in the blood of pregnant women using FACS, immunohistochemistry and spectratyping. We found an enrichment of activated and terminally differentiated pro-inflammatory γδ T-cell effectors with specific location in the human decidua during early pregnancy, while no significant changes in their counterparts in the blood of pregnant women were observed. Our spectratyping data revealed polyclonal CDR3 repertoires of the δ1, δ2 and δ3 chains and γ2, γ3, γ4 and γ5 chains and oligoclonal and highly restricted CDR3γ9 repertoire of γδ T cells in the decidua and blood of pregnant women. Early pregnancy induces recruitment of differentiated pro-inflammatory γδ T-cell effectors with diverse TCR repertoires at the maternal–fetal interface.

BACKGROUND: Successful implantation is a critical step for embryo survival. The major losses in natural and assisted human reproduction appeared to occur during the peri-implantation period. Because of ethical constraints, the fascinating maternal–fetal crosstalk during human implantation is difficult to study and thus, the possibility for clinical intervention is still limited. OBJECTIVE AND RATIONALE: This review highlights some features of human implantation as a unique, ineffective and difficult-to-model process and summarizes the pros and cons of the most used in vivo, ex vivo and in vitro models. We point out the variety of cell line-derived models and how these data are corroborated by well-defined primary cells of the same nature. Important aspects related to the handling, standardization, validation, and modus operandi of the advanced 3D in vitro models are widely discussed. Special attention is paid to blastocyst-like models recapitulating the hybrid phenotype and HLA profile of extravillous trophoblasts, which are a unique yet poorly understood population with a major role in the successful implantation and immune mother-embryo recognition. Despite raising new ethical dilemmas, extended embryo cultures and synthetic embryo models are also in the scope of our review. SEARCH METHODS: We searched the electronic database PubMed from inception until March 2024 by using a multi-stage search strategy of MeSH terms and keywords. In addition, we conducted a forward and backward reference search of authors mentioned in selected articles. OUTCOMES: Primates and rodents are valuable in vivo models for human implantation research. However, the deep interstitial, glandular, and endovascular invasion accompanied by a range of human-specific factors responsible for the survival of the fetus determines the uniqueness of the human implantation and limits the cross-species extrapolation of the data. The ex vivo models are short-term cultures, not relevant to the period of implantation, and difficult to standardize. Moreover, the access to tissues from elective terminations of pregnancy raises ethical and legal concerns. Easy-to-culture cancer cell lines have many limitations such as being prone to spontaneous transformation and lacking decent tissue characteristics. The replacement of the original human explants, primary cells or cancer cell lines with cultures of immortalized cell lines with preserved stem cell characteristics appears to be superior for in vitro modeling of human implantation and early placentation. Remarkable advances in our understanding of the peri-implantation stages have also been made by advanced three dimensional (3D) models i.e. spheroids, organoids, and assembloids, as placental and endometrial surrogates. Much work remains to be done for the optimization and standardization of these integrated and complex models. The inclusion of immune components in these models would be an asset to delineate mechanisms of immune tolerance. Stem cell-based embryo-like models and surplus IVF embryos for research bring intriguing possibilities and are thought to be the trend for the next decade for in vitro modeling of human implantation and early embryogenesis. Along with this research, new ethical dilemmas such as the moral status of the human embryo and the potential exploitation of women consenting to donate their spare embryos have emerged. The careful appraisal and development of national legal and ethical frameworks are crucial for better regulation of studies using human embryos and embryoids to reach the potential benefits for human reproduction. WIDER IMPLICATIONS: We believe that our data provide a systematization of the available information on the modeling of human implantation and early placentation and will facilitate further research in this field. A strict classification of the advanced 3D models with their pros, cons, applicability, and availability would help improve the research quality to provide reliable outputs.