Homeostatic cytokines regulate the emergence of human prenatal effector T cells

Abstract In a healthy pregnancy, prenatal immunity promotes tolerance in utero and transitions to provide protective immunity after birth. In pathologic pregnancies, in utero immune activation and the ensuing fetal inflammatory response are predictive of severe neonatal morbidity and mortality. We previously demonstrated that the majority of prenatal intestinal memory CD4 T cells express the transcription factor PLZF and possess a heightened Th1 effector potential. These PLZF+ CD4+ T cells specifically accumulate in the intestine, are absent from the adult, and are enriched in the cord blood of infants exposed to in utero inflammatory pathology. However, the signals that drive their intestinal accumulation and maturation are not well understood. We show that PLZF+ CD4+ T cells are MHC Class II restricted and display tissue specific functional heterogeneity, including Th2-, Th22- and Th17-like capacities. We provide evidence that differences in homeostatic cytokines between the small intestine and mesenteric lymph node support the preferential accumulation and functional compartmentalization of prenatal PLZF+ CD4+ T cells. Specifically, we show that IL-7 and TGFβ reciprocally modulate the preferential expansion and functional maturation of PLZF+ CD4+ T cells. We provide evidence for the generation of both virtual memory T cells as well as classic antigen driven differentiation of Th1- and Th17-like effector PLZF+ CD4+ T cells. This work identifies critical mechanisms of human prenatal immune maturation and regulation and could inform the development of novel therapeutic strategies to address perinatal inflammatory pathologies. Supported by K08 Mentored Clinical Scientist Development Award (AI128007) to Joanna Halkias and the Burroughs Wellcome Fund Preterm Birth Initiative (1019828)