CD38 expression by neonatal human naïve CD4+ T cells shapes their unique metabolic state and high regulatory T cell potential

Neonatal life is marked by rapid antigen exposure, necessitating establishment of peripheral immune tolerance via conversion of naïve CD4+ T cells into regulatory T cells (Tregs). Here, we demonstrate that increased Treg differentiation by naive CD4+ T cells from human cord blood versus adult blood is integrally linked to their unique metabolic profile and their elevated expression of the NADase, CD38. Early life naïve CD4+ T cells demonstrate a metabolic preference for glycolysis, which directly facilitates their Treg generation. We reveal an age-dependent gradient in CD38 levels on naïve CD4+ T cells and show that high CD38 expression contributes to both the glycolytic state and high Treg potential of neonatal CD4+ T cells, effects that are mediated at least in part via the NAD-dependent deacetylase SIRT1. Thus, the early life window for peripheral tolerance in humans is critically enabled by the immunometabolic state of the naïve CD4+ compartment.