CD8 T cells and heme oxygenase 1 interact to promote fetal tolerance and placental vascularization in pregnancy
Reproductive Medicine, Urology
Final Report Abstract
In pregnancies, the placenta and fetus carry allogenic molecules that are foreign to the mother. As such, they could be recognized and attacked by effector cells of the maternal immune system, e.g. the so called CD8+ T cells. To avoid this, induction of multiple mechanisms of immune tolerance is crucial and a matter of continues investigation, as failures may have consequences for the female and the offspring. Here, we investigated a subtype of CD8+ T cells with immune regulatory functions (CD8+Tregs), still not well characterized in the pregnant uterus. In mice, subtypes of CD8+ Tregs differentiated by either PD1 or Ly49 positivity, as well as CD8+ T cells seed the uterus during pregnancy and some clones proliferated. Sequencing of the full transcriptome at the single cell level and flow cytometry served to characterize CD8+ Treg subpopulations in depth. Uterine CD8+ T and Treg cells presented mixed memory and effector profiles. Using genetically modified mouse models and adoptive transfer of cells we demonstrated that CD8+ T and CD8+ Treg cells are likely to seed the uterus when they are specific for antigenic molecules in the conceptus. Accordingly, migrating cells express molecules in the membrane that provide adhesion to the endothelium. Adoptive transfer of CD8+ Tregs improved the obstetric outcome in recipient mice, by reducing the frequency of abortions and increasing the weight of the offspring. This last was likely due to enhanced vascularization of the placenta. Indeed, mice with preeclampsia-like syndrome, and hence impaired vascularization of the placenta, presented reduced Ly49 and PD1 positive CD8+ Tregs. These mechanisms may apply to human pregnancy, as we could recognize newly described CD8+ KIR+ Tregs in the pregnant uterus of women in early and late pregnancy. Taken together, CD8+ Tregs enhance obstetric outcomes and their reduction is associated to impaired placenta vascularization and pregnancy pathology. The fact that adoptive transfer of CD8+ Treg subsets can improve pregnancy outcome suggests interesting possibilities to treat pregnancy pathologies in the future, e.g. by means of cell therapy.
Publications
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CD8+ T cells in pregnancy: Characterization and function of uterine CD8+ T cells
Hardardottir, Lilja
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Decidual immune cells: Guardians of human pregnancies. Best Practice & Research Clinical Obstetrics & Gynaecology, 60, 3-16.
Solano, Maria Emilia
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Steroids, Pregnancy and Fetal Development. Frontiers in Immunology, 10.
Solano, Maria Emilia & Arck, Petra Clara
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The critical expansion of uterine CD8+ T cells in pregnancy is under tight homeostatic control
Hardardottier L., Bazzano M.V. & Solano M.E.
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The New Old CD8+ T Cells in the Immune Paradox of Pregnancy. Frontiers in Immunology, 12.
Hardardottir, Lilja; Bazzano, Maria Victoria; Glau, Laura; Gattinoni, Luca; Köninger, Angela; Tolosa, Eva & Solano, Maria Emilia
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16th ESRI Annual Meeting, Paris, 2022. J Rep Immunol 158, 2023. Postpartum uterine immunomodulation and tissue regeneration
Solano M.E., Hardardottir L. & Köninger A.
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Controlled recruitment and proliferation of placental specific CD8+ T cells in the pregnant uterus underlie fetal immune tolerance
L. Hardardottir, M.V. Bazzano & M.E. Solano
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Abundant macrophages and CD8+ T cells seed the postpartal uterus
Waldmann A., Hardardottir L. & Solano M.E.
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Regulatory CD8+ T cells are modulated in healthy and preeclampsia pregnancies
Shi W., Riedel A. & Solano M.E.
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Uterine enrichment of CD8+ T regulatory cells throughout pregnancy prevents fetal loss in mice. ISIR Young Investigator Award.
Hardardottir L., Bazzano M.V. & Solano M.E.
