Th160 - Regulation of Fetal Tolerance by KIR+CD8+ T Cells During Human Pregnancy

Purnima Narasimhan – Department of Obstetrics and Gynecology – Stanford University; Lin Li – Department of Obstetrics, Gynecology, and Reproductive Sciences, – University of California, San Francisco; Venkata Mallajosyula – Institute of Immunity, Transplantation and Infection – Stanford University; Mary Prunicki – Sean N. Parker Center for Allergy & Asthma Research – Stanford University; Kattria Van Der Ploeg – Department of Medicine – Stanford University; Adam Kirosingh – Department of Microbiology and Immunology – Stanford University; Prasanna Jagannathan – Department of Medicine – Stanford University; Kari Nadeau – Sean N. Parker Center for Allergy & Asthma Research – Stanford University; Stephanie Gaw – Department of Obstetrics, Gynecology, and Reproductive Sciences, – University of California San Francisco; Virginia Winn – Department of Obstetrics and Gynecology – Stanford University; Mark Davis – Institute of Immunity, Transplantation and Infection – Stanford University

Abstract Text: Immune responses during pregnancy need to be precisely regulated to protect the fetus from microbial infections and to maintain tolerance for the semi-allogeneic fetus. However, the mechanisms regulating fetal tolerance during pregnancy are not well understood. Recently, we have identified KIR+CD8+ T cells as a previously unappreciated subset with regulatory functions in humans to suppress harmful self-reactivity. Therefore, we asked whether KIR+CD8+ T cells also function to induce immune tolerance during pregnancy. We first observed an increased frequency of KIR+CD8+ T cells in the peripheral blood of pregnant women at second trimester compared to age-matched nonpregnant females. Moreover, those with a male fetus had an even higher level of KIR+CD8+ T cells than the ones with a female fetus. In vitro, we found that KIR+CD8+ T cells can suppress HY-specific CD8+ T cells only in mothers with a male fetus. Therefore, the higher induction of KIR+CD8+ T cells in mothers carrying a male fetus may suppress the additional allogenic immune responses triggered by the Y chromosome from the male fetus. As revealed by the longitudinal analysis, KIR+CD8+ T cells expand, lose memory features and become cytotoxic along gestation and their levels are maintained postnatally. Last, we found increase of KIR+CD8+ T cells correlated with pregnancy disorders (e.g., spontaneous abortion and pre-eclampsia). Taken together, our findings suggest an important role of KIR+CD8+ T cells in the maintenance of fetal tolerance by suppressing alloreactive fetus-specific T cells, therefore they may be useful as predictive biomarkers or drug targets for human pregnancy disorders.