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.

doi:10.1101/2025.01.02.631038

bioRxiv · 10.1101/2025.01.02.631038

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.

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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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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.. 2025-01-02. CD38 expression by neonatal human naïve CD4+ T cells shapes their distinct metabolic state and high regulatory T cell potential. https://doi.org/10.1101/2025.01.02.631038

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