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

在怀孕期间，母亲的生理适应确保了成长中的胎儿获得营养和氧气，同时避免了对半异基因胎盘滋养层细胞的有害免疫反应。我们以前观察到，在产前应激暴露的情况下，免疫耐受的破坏会导致炎症和细胞毒性反应、胎盘功能不全和宫内生长受限(IUGR)。这种变化与胎盘中血红素代谢酶血红素加氧酶1(HMOX-1)的表达减少以及具有调节功能的CD8CD122 T细胞(CD8 Treg细胞)的频率降低有关。我们可以证明小鼠CD8 Treg细胞对HMOX-1水平有很高的反应。此外，过继转移CD8 Treg细胞可以预防因HMOX-1水平降低而影响的植入中的胎盘功能不全和IUGR。在本研究中，我们假设HMOX-1和CD8 T细胞的相互作用促进了免疫耐受和胎盘的血管形成。为了验证这一假设，我们首先旨在全面表征在小鼠怀孕期间基本上未被研究的CD8 Treg细胞的表达谱和功能。我们将使用最先进的技术，例如单细胞水平的CD8 T细胞转录组测序和Luminex细胞因子和血管生成介质的测定。其次，将使用体外和体内方法明确地剖析CD8 Treg细胞在胎盘中促进血管生成的过程。鉴于HMOX-1支持CD8 Treg细胞的扩增，我们将再次深入研究胎盘HMOX-1表达对CD8 Treg细胞功能的影响。最后，我们的目标是筛选CD8 Treg细胞亚群，这些亚群可能是人类和小鼠妊娠中HMOX-1衍生多肽的特异性亚群。我们预见，HMOX-1-CD8 Treg介导的胎儿耐受和胎盘发育机制的全面表征将为早期识别IUGR高危妊娠提供机会，并为治疗干预提供场所。

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.