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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
Published June 22, 2009
Citation Information: J Clin Invest. 2009;119(7):2062-2073. https://doi.org/10.1172/JCI38714.
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Research Article

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

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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 1

Identification of migratory DCs in the nonpregnant uterus.

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Identification of migratory DCs in the nonpregnant uterus.
(A) A basic g...
(A) A basic gating scheme to identify uterine DCs. Viable leukocytes were visualized using anti-CD45 antibodies in combination with the nucleic acid dye 7-aminoactinomycin D (7-AAD) to exclude dead cells. MHCII+F4/80– cells divided into 2 putative DC subsets with CD11c+CD11blo and CD11c+CD11bhi surface phenotypes; MHCII+F4/80+ cells were CD11clo. The diagonal arrow indicates an MHCII–F4/80+ population largely consisting of eosinophils based upon their high side scatter characteristics (data not shown). (B) Cell-surface marker expression by MHCII+F4/80– DC subsets (red histograms). Black histograms show isotype control staining. (C and D) CCR7-dependent arrival of CFSE+ cells in the uterine LNs after CFSE labeling the uterus in situ. Flow cytometric analysis of total uterine cell suspensions (C) and respective uterine LN cells (D) 28 hours after transcervical CFSE injection. The plots are gated on alive CD45+ cells, and the percentage of CD45+ MHCII+ cells that are CFSE+ is indicated. Data are representative of n = 4–6 mice per group. (E) Cell-surface marker profiles of CFSEbright cells in the uterine LNs. CFSEbright gated cells (fuchsia) are show in the lower 4 panels overlaying the general distribution of DCs gated as indicated. In addition, CFSEbright cells did not express F4/80, Ly-6C, or Gr-1 (data not shown). In confirmation of the paraaortic and renal LNs being the draining LN of the murine uterus, only these LNs accumulated CFSEbright cells following transcervical CFSE injection into wild-type mice.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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