Maternal T Cells in the Human Placental Villi Support an Allograft Response during Noninfectious Villitis

Abstract

During human pregnancy, proinflammatory responses in the placenta can cause severe fetal complications, including growth restriction, preterm birth, and stillbirth. Villitis of unknown etiology (VUE), an inflammatory condition characterized by the non-infectious infiltration of maternal CD8+ T cells into the placenta, is hypothesized to be secondary to either a tissue rejection response to the haploidentical fetus or from an undiagnosed infection. Here we characterized the global T cell receptor (TCR) beta chain profile in human placental T cells diagnosed with VUE compared to control and infectious villitis diagnosed placentae by immunoSEQ. Deep sequencing demonstrated that VUE is driven predominantly by maternal T cell infiltration, which is significantly different from controls and infectious cases; however, these T cell clones show very little overlap between subjects. Mapping TCR clones to common viral epitopes (cytomegalovirus [CMV], Epstein-Barr virus and influenza A) demonstrated that antigen specificity in VUE was equal to controls and significantly lower than CMV-specific clones in infectious villitis. Our data indicate VUE is an allograft response, not an undetected infection. These observations support the development of screening methods to predict those at risk of VUE and the use of specific immunomodulatory therapies during gestation to improve outcomes in affected fetuses.