CD8 T cells and heme oxygenase 1 interact to promote fetal tolerance and placental vascularization in pregnancy

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During pregnancy maternal physiological adaptations ensure that the growing fetus is provided with nutrients and oxygen, while deleterious immune responses against the semiallogeneic placental trophoblast are avoided. We previously observed that in the case of prenatal stress exposure, break of immune tolerance results in inflammation and cytotoxic responses, placental insufficiency and intrauterine growth restriction (IUGR). This changes are associated to decreased placental expression of the heme metabolizing enzyme heme oxygenase 1 (HMOX-1) as well as decreased frequencies of CD8CD122 T cells with a regulatory function (CD8 Treg cells). We could demonstrate that murine CD8 Treg cells are highly responsive to HMOX-1 levels. Moreover, adoptive transfer of CD8 Treg cells prevented placental insufficiency and IUGR in implantations affected by reduced HMOX-1 levels.In the present proposal we hypothesize that HMOX-1 and CD8 T cell interactions promote immune tolerance and the vascularization of the placenta. To test this hypothesis, we first aim to comprehensively characterize the largely uninvestigated CD8 Treg cell expression profile and function in murine pregnancies. We will use state of the art techniques, such as CD8 T cell transcriptome sequencing at the single cell level and Luminex determination of cytokines and angiogenic mediators. Secondly, ex vivo and in vivo approaches will be employed to unambiguously dissect the angiogenic processes promoted by CD8 Treg cell in the placenta. Given that HMOX-1 sustains the expansion of CD8 Treg cells, we will thirdly characterize in depth the effect of placental HMOX-1 expression on CD8 Treg cell function. Finally we aim to screen for subpopulations of CD8 Treg cells that may be specific for HMOX-1 derived peptides in human as well as in mouse pregnancies. We envision that a comprehensive characterization of HMOX-1-CD8 Treg mediated mechanisms for fetal tolerance and placental development will open opportunities for the early identification of pregnancies at risk for IUGR as well as venues for therapeutical interventions.