Institute of Immunology, Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany.
Molecular Physiology and Biophysics Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
Reproduction. 2020 Nov;160(5):685-694. doi: 10.1530/REP-20-0277.
In early equine pregnancy, a highly invasive trophoblast cell subpopulation, the chorionic girdle cells, invade the endometrium and form endometrial cups (EC). These cells express classical MHC molecules, thereby stimulating a humoral and cellular immune response, resulting in a massive accumulation of maternal CD4+ and CD8+ T cells around the EC. Nevertheless, no immediate destruction of endometrial cups by maternal lymphoid cells occurs, presumably due to immune tolerance. Although the environment of EC is rich in TGFB and in FOXP3+, CD4+ T cells, the mechanisms leading to tolerance have not been elucidated. Recently, we discovered that equine trophoblast cells secrete pregnancy-specific glycoproteins (PSGs). Since human and murine PSGs activate latent TGFB, we hypothesized that equine PSGs may have a similar activity. We performed plasmon surface resonance experiments to show that equine PSG CEACAM49 can directly bind to the latency-associated peptide (LAP) of both TGFB1 and TGFB2. We then found that the binding of CEACAM49 leads to the activation of TGFB1 as determined by both ELISA and cell-based assays. Furthermore, the activation of TGFB is a unique function of PSGs within the human CEA family, because CEACAM1, 3, 5, 6, 8 do not activate this cytokine. This finding further strengthens the classification of CEACAM49 as an equine PSG. Based on our results, we hypothesize that activation of latent TGFB in the EC environment by equine PSGs secreted by invasive trophoblast cells, could contribute to the generation of regulatory T cells (Tregs) to maintain immune tolerance.
在马早期妊娠中，一种高度侵袭性的滋养层细胞亚群，即绒毛膜带细胞，侵入子宫内膜并形成子宫内膜杯（EC）。这些细胞表达经典的 MHC 分子，从而刺激体液和细胞免疫反应，导致大量母源 CD4+和 CD8+T 细胞围绕 EC 积聚。然而，母源淋巴细胞并没有立即破坏子宫内膜杯，这可能是由于免疫耐受。尽管 EC 的环境富含 TGFB 和 FOXP3+，但 CD4+T 细胞，导致耐受的机制尚未阐明。最近，我们发现马的滋养层细胞分泌妊娠特异性糖蛋白（PSGs）。由于人和鼠的 PSGs 激活潜伏的 TGFB，我们假设马的 PSGs 可能具有类似的活性。我们进行等离子体表面共振实验表明，马的 PSG CEACAM49 可以直接结合 TGFB1 和 TGFB2 的潜伏相关肽（LAP）。然后，我们发现 CEACAM49 的结合导致 TGFB1 的激活，这通过 ELISA 和基于细胞的测定得到证实。此外，TGFB 的激活是人类 CEA 家族中 PSGs 的独特功能，因为 CEACAM1、3、5、6、8 不会激活这种细胞因子。这一发现进一步证实了 CEACAM49 被归类为马 PSG。基于我们的结果，我们假设由侵袭性滋养层细胞分泌的马 PSGs 激活 EC 环境中的潜伏 TGFB，可能有助于产生调节性 T 细胞（Tregs）以维持免疫耐受。
