Human fetal and neonatal naïve CD4+ T cells are bound for intestinal migration and display a gut-associated activation-prone profile

Whether naïve T cells could manifest tissue-specific functional heterogeneity remains largely unexplored. Here, we characterized human naïve CD4+ T cells in the fetal (mid-gestation), pediatric (3-17 years) and adult (27-41 years) intestinal mucosa in comparison to circulation.

We found that intestinal naïve T cells across ages retain a transcriptionally naïve identity, but display a more activation-prone profile. This state was most pronounced in the fetus, where intestinal naïve T cells shared an activation-prone, early differentiation profile with the mesenteric lymph node. Notably, in the fetal intestine this activation-prone naïve state co-occurred with tissue-adapted Tregs and extensively differentiated effector/memory T cells with TCR features consistent with an early developmental origin.