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. 2021 Feb 25:12:642392.
doi: 10.3389/fimmu.2021.642392. eCollection 2021.

Crosstalk Between Trophoblasts and Decidual Immune Cells: The Cornerstone of Maternal-Fetal Immunotolerance

Affiliations

Crosstalk Between Trophoblasts and Decidual Immune Cells: The Cornerstone of Maternal-Fetal Immunotolerance

Ling Xu et al. Front Immunol. .

Abstract

The success of pregnancy relies on the fine adjustment of the maternal immune system to tolerate the allogeneic fetus. Trophoblasts carrying paternal antigens are the only fetal-derived cells that come into direct contact with the maternal immune cells at the maternal-fetal interface. The crosstalk between trophoblasts and decidual immune cells (DICs) via cell-cell direct interaction and soluble factors such as chemokines and cytokines is a core event contributing to the unique immunotolerant microenvironment. Abnormal trophoblasts-DICs crosstalk can lead to dysregulated immune situations, which is well known to be a potential cause of a series of pregnancy complications including recurrent spontaneous abortion (RSA), which is the most common one. Immunotherapy has been applied to RSA. However, its development has been far less rapid or mature than that of cancer immunotherapy. Elucidating the mechanism of maternal-fetal immune tolerance, the theoretical basis for RSA immunotherapy, not only helps to understand the establishment and maintenance of normal pregnancy but also provides new therapeutic strategies and promotes the progress of immunotherapy against pregnancy-related diseases caused by disrupted immunotolerance. In this review, we focus on recent progress in the maternal-fetal immune tolerance mediated by trophoblasts-DICs crosstalk and clinical application of immunotherapy in RSA. Advancement in this area will further accelerate the basic research and clinical transformation of reproductive immunity and tumor immunity.

Keywords: decidual immune cells; immunotherapy; maternal-fetal immunotolerance; recurrent spontaneous abortion; trophoblasts.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Differentiation and development of trophoblasts. The blastocyst developed from the fertilized egg further differentiates into inner cell mass (ICM) and trophectoderm (TE). ICM develops into the fetus, while TE differentiates into cytotrophoblasts (CTBs or villous cytotrophoblasts, VCTs) which further differentiate into syncytiotrophoblasts (STBs or SCTs) and extravillous trophoblasts (EVTs). The EVTs that invade the decidua can be divided into intravascular EVTs (enEVTs) and interstitial EVTs (iEVTs) according to the specific location. EGFR, epidermal growth factor receptor; NRP2, neuropilin-2; HGFR, hepatocyte growth factor receptor; ACKR2, atypical chemokine receptor 2; HLA, human leukocyte antigen; CXCR6, C-X-C chemokine receptor type 6.
Figure 2
Figure 2
A diagram of the maternal-fetal interface in the first trimester. The thick lines surrounding CTBs represent STBs. Area A indicates the floating villi and interstitial spaces. Area B represents the villous column formed by trophoblasts. Area C represents the decidua layer. Area D indicates the myometrium. The important maternal-fetal interface is composed of EVTs, DSCs, and decidual immune cells. CTB, cytotrophoblast; enEVT, endovascular EVT; iEVT, interstitial EVT; pNK, peripheral natural killer cell; pT, peripheral T cell; Mo, monocyte; RBC, red blood cell; EC, endothelial cell; dMΦ, decidual macrophages; dNK, decidual natural killer cell; dT, decidual T cel; DSC, decidual stromal cell.
Figure 3
Figure 3
The interaction between HLA ligands on EVTs and inhibitory receptors on dNK cells. The pattern diagram shows the expression profile of HLA antigens on EVTs and the corresponding inhibitory receptors on dNK cells. All inhibitory receptors contain at least one ITIM motif in their intracellular regions. EVT, extravillous trophoblasts; HLA, human leukocyte antigen; dNK, decidual natural killer cell; KIR, killer cell immunoglobulin receptor; LILRB1, leukocyte immunoglobulin-like receptor subfamily B member 1; ILT2, immunoglobulin-like transcript 2.
Figure 4
Figure 4
Mechanisms of the M2 polarization of decidual macrophages by trophoblasts. Tros express chemokine CXCL16, extracellular matrix HA, cytokines (RANKL, IL-6, IL-10, M-CSF, and IL-34), and checkpoint ligands PD-L1 and sPD-L1, which act on macrophages to promote them to polarize toward M2 phenotype via different signal pathways. Tros, trohoblasts; CXCL16, C-X-C motif chemokine ligand 16; RANKL, receptor activator for nuclear factor-κ B ligand; HA, hyaluronic acid; IL, interleukin; M-CSF, macrophages colony stimulating factor; sPD-L1, soluble programmed cell death 1 ligand 1; sHLA-G, soluble human leukocyte antigen G; CXCR6, C-X-C chemokine receptor type 6; RANK, receptor activator for nuclear factor-κ B; STAT, signal transducer and activator of transcription.
Figure 5
Figure 5
Effects of trophoblasts on decidual T lymphocytes to form the immunotolerance. Tros promote the apoptosis of activated T cells through IDO and inhibit the cytotoxicity of CD8+ T cells via HLA-C and PD-L1. Th2 bias and Treg expansion induced by trophoblasts via multiple mechanisms are summarized in this diagram. Tros, trohoblasts; IDO, indoleamine 2,3-dioxyenase; TSLP, thymic stromal lymphopoietins; TGF-β, transforming growth factor-β; IL, interleukin; TRAIL, TNF-related apoptosis-inducing ligand; HLA, human leukocyte antigen; PD-L1, programmed cell death 1 ligand 1.

References

    1. Gellersen B, Brosens JJ. Cyclic decidualization of the human endometrium in reproductive health and failure. Endocr Rev. (2014) 35:851–905. 10.1210/er.2014-1045 - DOI - PubMed
    1. Brosens I, Puttemans P, Benagiano G. Placental bed research: I. The placental bed: from spiral arteries remodeling to the great obstetrical syndromes. Am J Obstet Gynecol. (2019) 221:437–56. 10.1016/j.ajog.2019.05.044 - DOI - PubMed
    1. Billingham RE, Brent L, Medawar PB. Actively acquired tolerance of foreign cells. Nature. (1953) 172:603–6. 10.1038/172603a0 - DOI - PubMed
    1. Zhang J, Mo HQ, Tian FJ, Zeng WH, Liu XR, Ma XL, et al. . EIF5A1 promotes trophoblast migration and invasion via ARAF-mediated activation of the integrin/ERK signaling pathway. Cell Death Dis. (2018) 9:926. 10.1038/s41419-018-0971-5 - DOI - PMC - PubMed
    1. Ma XL, Li X, Tian FJ, Zeng WH, Zhang J, Mo HQ, et al. . Upregulation of RND3 affects trophoblast proliferation, apoptosis, and migration at the maternal-fetal interface. Front Cell Dev Biol. (2020) 8:153. 10.3389/fcell.2020.00153 - DOI - PMC - PubMed

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