Pregnancy promotes tolerance to future offspring by programming selective dysfunction in long-lived maternal T cells.
Fetal antigen available during pregnancy induces the proliferation of maternal T cells. It is unknown, however, whether these antigen-activated T cells differentiate into long-lived memory T cells that are capable of mediating rapid-recall responses to tissue antigens. To test the hypothesis that pregnancy induces an alternative fate in fetal-specific maternal T cells, we used a murine model to track longitudinally fetal-specific T cells in pregnant and postpartum animals and test the response of these cells when challenged with the same antigen during sequential pregnancy or skin transplantation. Fetal-specific CD8+T cells were robustly primed during pregnancy but failed to acquire robust effector functions. These primed cells persisted long term in postpartum animals, frequently maintained a programmed death 1 (PD-1)+phenotype, and failed to expand or produce cytokines robustly in response to second pregnancy or skin transplantation. However, whereas there was no impact on second pregnancy as a result of the persistence of fetal-primed memory CD8+T cells in the mother, skin grafts bearing the same antigen were rejected more rapidly. Altogether, our data suggest that fetal antigen exposure during pregnancy induces the differentiation of long-lived maternal CD8+T cells with context-dependent, selective effector dysfunction. This programmed effector dysfunction provides temporal and systemic restraint of maternal anti-fetal alloreactivity to promote reproductive fitness efficiently, while preserving potentially protective effector T cell responses.
Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
Brendan M
BM
Barton
Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; and.
Rong
R
Xu
Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
E John
EJ
Wherry
Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; and paige.porrett@uphs.upenn.edu.
Paige M
PM
Porrett
D000818:Animals; D000941:Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D002454:Cell Differentiation; D002470:Cell Survival; D016922:Cellular Senescence; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D005333:Fetus / Q000166:cytology; D006084:Graft Rejection / Q000276:immunology; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D016038:Skin Transplantation; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology
D000941:Antigens; D016207:Cytokines
PD-1; alloimmunization; exhaustion; fetomaternal; transplantation