Fetoplacental extracellular vesicles deliver conceptus-derived antigens to maternal secondary lymphoid tissues for immune recognition
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
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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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 7

T cells in the maternal spleen recognize paternal Ag on trophoblast sEVs.

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T cells in the maternal spleen recognize paternal Ag on trophoblast sEVs...
(A) Flow cytometry of proliferation of i.v. injected, CFSE-labeled OT-I CD8 T cells (CD90.1) in spleens of WT virgin female B6 mice (CD90.2) i.v. injected 24 hours later with EV-cleared supernatants or intact or lysed sEVs from cultures of trophoblast cells from BALB/c females impregnated with mOVA B6 or control WT B6 males. On the dot plot on the right, each dot represents 1 mouse. (B) Representative flow cytometry of splenocytes of B6 virgin females (CD90.2) i.v. injected with CFSE-labeled OT-I CD8+ T cells (CD90.1) and treated i.v. 24 hours later with sEVs from primary trophoblast culture supernatants from BALB/c females impregnated with mOVA B6 males or control WT B6 males. As a positive control of OT-I cell activation, a group was injected i.p. with soluble OVA + agonistic CD40 Ab + poly I:C, 24 hours after the OT-I cell transfer. Experiments were analyzed 2 days after sEV injection. (C) Quantification of the results shown in B; each dot represents 1 mouse. (D) FACS analysis of i.v. administered OT-I T cells (CD90.1) in spleens of females (CD90.2) mated with mOVA or WT B6 male mice. OT-I T cells were i.v. infused on E13.5, and splenocytes were FACS-analyzed 2 days later. (E) Quantification of the results in D; each dot represents 1 mouse. In A and C, comparisons by 1-way ANOVA with multiple comparisons. In E, comparisons by 2-tailed Student’s test. Error bars: means ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.001.