Peripheral Regulatory T Cells Display Dynamic Memory Subset Frequency and Inhibitory Marker Expression Across Pregnancy

ABSTRACT Problem Pregnancy is characterized by significant changes in peripheral immunity. Total CD3+ T cells decrease across pregnancy while Forkhead Box P3+ T‐regulatory cells (FoxP3+Tregs) peak in mid‐pregnancy, the latter of which are key to healthy outcomes. However, less is known regarding distinct memory populations of FoxP3+ Tregs and their phenotypic changes across pregnancy. Method Of Study Pregnant individuals were enrolled into a prospective cohort study and high parameter flow cytometry was used to characterize peripheral blood mononuclear cells collected at first and second trimester and delivery. Memory and phenotypic marker expression on FoxP3+ Tregs at each timepoint were analyzed. Non‐Treg CD4+ T cells and CD8+ Tcells were assessed as comparison populations. Suppressive capacity of FoxP3+ Tregs was compared between first trimester and delivery. Results The frequency of central and effector memory populations within FoxP3+ Tregs, non‐Treg CD4+ T cells, and CD8+ T cells decreased across pregnancy ( p ≤ 0.001 for all). Inducible T cell Costimulator (ICOS) expression decreased on FoxP3+ Tregs across pregnancy ( p = 0.01), while T cell immunoglobulin and mucin domain‐containing protein 3 (Tim3) expression increased on FoxP3 Tregs, non‐Treg CD4+, and CD8+ T cells ( p ≤ 0.005 for all). Suppressive capacity of Tregs did not vary by gestational timepoint. Conclusions We observed an increase in naïve cells in FoxP3+ and non‐Treg CD4+ T cells across gestation and a corresponding reduction in ICOS expression. However, the observed increase in Tim3 expression on all T cell subsets suggests a dissociation between suppressive markers in pregnancy. Together, these data suggest that pregnancy has a unique impact on Treg memory distribution and phenotype.