CD38 expression by neonatal human naïve CD4+ T cells shapes their distinct metabolic state and high regulatory T cell potential
Dwyer, L. R.; Clancy, S.; Gouirand, V.; Chien, C.; Rogers, E. E.; Oltman, S. P.; Jelliffe-Pawlowski, L. L.; Lynch, S. V.; Wagner, A.; Combes, A. J.; Scharschmidt, T. C.
Show abstract
Neonatal life is marked by rapid antigen exposure, necessitating establishment of peripheral immune tolerance via conversion of naive 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 naive 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 naive 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 naive CD4+ compartment.
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