PhD candidate Univ. of Cincinnati Col. of Med., United States
Disclosure(s):
Shweta Mahajan, MSc: No financial relationships to disclose
Introduction/Rationale: During pregnancy, maternal CD8 T cells must balance the competing needs of immunity and maternal-fetal tolerance. In contrast to blood CD8 T cells, decidual CD8 T cells at the maternal-fetal interface have decreased expression of cytolytic molecules perforin and granzyme B. This suggests that the decidual environment shapes CD8 T cell differentiation and effector functions.
Methods: To test the hypothesis that to maintain maternal-fetal tolerance, extravillous trophoblasts (EVT) suppress CD8 T cell cytotoxicity, CD8 T cells were stimulated with anti-CD3/CD28 in the absence or presence of EVT for three days. High dimensional flow cytometry and RNA-sequencing were used to define the of loss cytolytic granule expression as well as the mechanisms underpinning the loss of cytotoxic functions. Decidual stromal cell (DSC) co-cultures were used as cellular controls in parallel co-cultures.
Results: Co-culture with EVT, but not DSC, significantly reduced both the expression and secretion of perforin and granzyme B in activated CD8 T cells, highlighting the suppressive influence of EVT on CD8 T cells cytotoxic function. Furthermore, in trans well experiments that prevented cell-cell contact between EVT and CD8 T cells left the suppression of Perforin and Granzyme B largely intact, suggesting that the suppressive mechanism include soluble factors. Addition of TGF-beta and TGF-beta Receptor blocking antibodies did not influence the suppression of the cytolytic granules. Current transcriptomic analysis is focused to define the drivers of perforin and granzyme B suppression in CD8 T cells by EVT.
Conclusion: Understanding how fetal EVT interact with maternal T cells and regulate CD8 T cell cytotoxicity is critical to define mechanisms of tolerance in healthy human pregnancy. Subsequently elucidating the defects and their roles in placental inflammation & infection will directly contribute to the identification of therapeutic targets to resolve placental inflammation and infection.
