CD38 expression by neonatal human naïve CD4 ⁺ T cells shapes their distinct metabolic state and tolerogenic 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 heighted capacity for FOXP3 expression and tolerogenic function among cord blood versus adult blood naive CD4 ⁺ T cells and that this is linked to their unique metabolic profile and elevated expression of the NADase, CD38. Early life naïve CD4 ⁺ T cells demonstrate a metabolic preference for glycolysis, which directly facilitates their differentiation trajectory. 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 tolerogenic 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.