Fetoplacental extracellular vesicles deliver conceptus-derived antigens to maternal secondary lymphoid tissues for immune recognition
Juliana S. Powell, … , Yoel Sadovsky, Adrian E. Morelli
Juliana S. Powell, … , Yoel Sadovsky, Adrian E. Morelli
Published May 22, 2025
Citation Information: JCI Insight. 2025;10(10):e186335. https://doi.org/10.1172/jci.insight.186335.
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Research Article Immunology Reproductive biology

Fetoplacental extracellular vesicles deliver conceptus-derived antigens to maternal secondary lymphoid tissues for immune recognition

Abstract

Pregnancy is an immunological paradox where despite a competent maternal immune system, regulatory mechanisms at the fetoplacental interface and maternal secondary lymphoid tissues (SLTs) circumvent rejection of semi-allogeneic concepti. Small extracellular vesicles (sEVs) are a vehicle for intercellular communication; nevertheless, the role of fetoplacental sEVs in transport of antigens to maternal SLTs has not been conclusively demonstrated. Using mice in which the conceptus generates fluoroprobe-tagged sEVs shed by the plasma membrane or released from the endocytic compartment, we show that fetoplacental sEVs are delivered to immune cells in the maternal spleen. Injection of sEVs from placentas of females impregnated with Act-mOVA B6 males elicited suboptimal activation of OVA-specific CD8+ OT-I T cells in virgin females as occurs during pregnancy. Furthermore, when OVA+ concepti were deficient in Rab27a, a protein required for sEV secretion, OT-I cell proliferation in the maternal spleen was decreased. Proteomics analysis revealed that mouse trophoblast sEVs were enriched in antiinflammatory and immunosuppressive mediators. Translational relevance was tested in humanized mice injected using sEVs from cultures of human trophoblasts. Our findings show that sEVs deliver fetoplacental antigens to the mother’s SLTs that are recognized by maternal T cells. Alterations of such a mechanism may lead to pregnancy disorders.

Authors

Juliana S. Powell, Adriana T. Larregina, William J. Shufesky, Mara L.G. Sullivan, Donna Beer Stolz, Stephen J. Gould, Geoffrey Camirand, Sergio D. Catz, Simon C. Watkins, Yoel Sadovsky, Adrian E. Morelli

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Figure 9

Reduction of release of fetoplacental sEVs decreases maternal T cell recognition of paternal Ag.

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Reduction of release of fetoplacental sEVs decreases maternal T cell rec...
(A) Assessment by NTA of sEVs per trophoblast cell in supernatants of cultures of B6 mouse trophoblasts, WT or Rab27aKO. Each dot represents sEVs from a different culture. (B) Proliferation of CFSE-labeled OT-I CD8+ T cells (CD90.1) in spleens of WT or Rab27aKO B6 females (CD90.2) mated with mOVA B6 or mOVA Rab27aKO B6 males. OT-I cells were i.v. injected on E15.5 and splenocytes analyzed by FACS on E17.5. Dot plot (right): percentages of dividing OT-I cells, where each dot represents 1 mouse. (C) Division of CFSE-labeled OT-I cells (CD90.1) in spleens of WT or Rab27aKO B6 virgin females injected i.v. with sEVs from trophoblast cultures of E17.5 placentas from BALB/c females impregnated with mOVA B6 males. Dot plot (right): percentages of proliferating OT-I cells, where each dot represents 1 mouse. Splenocytes were analyzed by FACS 2 days after transfer of OT-I cells and injection of trophoblast sEVs. (D) Percentages of proliferation of CFSE-labeled OT-I cells (CD90.1) in spleens of B6 females impregnated with WT or mOVA B6 males, assessed by FACS on successive days PP. Each dot represents 1 mouse. (E) Microscopy of CD81-mNeonGreen in FDCs in B cell follicles on cryosections of spleens of CMVCre/+ or CMV– B6 females, impregnated with Exomap1 B6 males and analyzed PP. Original magnification, ×200, ×400. (F) IEM showing OVA-bearing sEVs in maternal CD21/35+ FDCs on an ultrathin cryosection of a spleen of a WT B6 female impregnated with a mOVA B6 male and analyzed on day 7 PP. Representative of 2 spleens analyzed. Original magnification, ×20,000, ×80,000. In A, comparisons by 2-tailed Student’s test. In B–D, comparisons by 1-way ANOVA with multiple comparisons. Error bars: means ± SD. *P < 0.05, **P < 0.01.