Dendritic cell entrapment within the pregnant uterus inhibits immune surveillance of the maternal/fetal interface in mice
Mary K. Collins, Chin-Siean Tay, Adrian Erlebacher
Mary K. Collins, Chin-Siean Tay, Adrian Erlebacher
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Research Article

Dendritic cell entrapment within the pregnant uterus inhibits immune surveillance of the maternal/fetal interface in mice

Abstract

Embryo implantation induces formation of the decidua, a stromal cell–derived structure that encases the fetus and placenta. Using the mouse as a model organism, we have found that this tissue reaction prevents DCs stationed at the maternal/fetal interface from migrating to the lymphatic vessels of the uterus and thus reaching the draining lymph nodes. Strikingly, decidual DCs remained immobile even after being stimulated with LPS and exhibiting responsiveness to CCL21, the chemokine that drives DC entry into lymphatic vessels. An analysis of maternal T cell reactivity toward a surrogate fetal/placental antigen furthermore revealed that regional T cell responses toward the fetus and placenta were driven by passive antigen transport and thus the tolerogenic mode of antigen presentation that predominates when there is negligible input from tissue-resident DCs. Indeed, the lack of involvement of tissue-resident DCs in the T cell response to the fetal allograft starkly contrasts with their prominent role in organ transplant rejection. Our results suggest that DC entrapment within the decidua minimizes immunogenic T cell exposure to fetal/placental antigens and raise the possibility that impaired development or function of the human decidua, which unlike that of the mouse contains lymphatic vessels, might lead to pathological T cell activation during pregnancy.

Authors

Mary K. Collins, Chin-Siean Tay, Adrian Erlebacher

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Figure 5

DC dynamics in the pregnant uterus.

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DC dynamics in the pregnant uterus. (A) Cell number per implantation sit...
(A) Cell number per implantation site and cell number per milligram tissue (i.e., tissue density) for all DCs (sum of the v and vi gates of Figure 4) and all possible myeloid APCs (sum of the iii, iv, v, and vi gates of Figure 4). Data show mean ± SEM for n = 4–7 mice per group. *P < 0.05, **P < 0.02, ***P < 0.005 versus decidua. NA, not applicable. (B) Spatial distribution of uterine DCs during pregnancy. Transverse sections, with their mesometrial poles oriented upward, were double stained with antibodies against MHCII (green) and CD11c (red) and counterstained with DAPI. Single-channel images and combined MHCII/CD11c images after their “AND” gating (Double+ cells; see Methods) are shown in black and white. Uterine lumens are outlined with solid white lines, and orange dashed lines demarcate the undecidualized endometrium (e) from the myometrium (m) or the decidua (dec) from the myometrium (myo). The arrows indicate groups of trophoblasts lateral to implanted embryos. The asterisk indicates nonspecific staining. To visualize DCs in panoramic view, we manipulated the images as described in Methods; some are shown at higher magnification in Supplemental Figure 5. Scale bars: 1 mm. (C) Uterine DC densities in wild-type versus Ccr7–/– mice. Tissue densities in virgin mice, determined by histomorphometry, are shown as mean ± SD of n = 3 mice per group; densities on E10.5, determined by flow cytometry, are shown as mean ± SEM of n = 3–4 mice per group.