CD38 expression by neonatal human naive CD4+ T cells shapes their distinct metabolic and tolerogenic properties

  • J Clin Invest. 2026 Feb 26;136(8):e200062. doi: 10.1172/JCI200062.
Laura R Dwyer  1  2 ,  Andrea M DeRogatis  2 ,  Sean Clancy  2 ,  Victoire Gouirand  2 ,  Charles Chien  3  4 ,  Elizabeth E Rogers  5  6 ,  Scott P Oltman  5  7  8  9 ,  Laura L Jelliffe-Pawlowski  5  7  8  9  10  11 ,  Theo van den Broek  12 ,  Femke van Wijk  12 ,  Susan V Lynch  13  14 ,  Rachel L Rutishauser  15 ,  Allon Wagner  3  4  16 ,  Alexis J Combes  17 ,  Tiffany C Scharschmidt  2
Affiliations
  • 1. Biomedical Sciences Graduate Program, and.
  • 2. Department of Dermatology, UCSF, San Francisco, USA.
  • 3. Department of Electrical Engineering and Computer Sciences, and.
  • 4. Center for Computational Biology, University of California, Berkeley, Berkeley, USA.
  • 5. Healthy Outcomes of Pregnancy for Everyone Research Consortium.
  • 6. Department of Pediatrics.
  • 7. Department of Epidemiology and Biostatistics.
  • 8. Department of Global Health Sciences, and.
  • 9. California Preterm Birth Initiative, UCSF, San Francisco, USA.
  • 10. Rory Meyers College of Nursing, New York University, New York, New York, USA.
  • 11. EGG Healthy Pregnancy, San Francisco, California, USA.
  • 12. Center for Translational Immunology, University Medical Centre Utrecht, Utrecht University, Netherlands.
  • 13. Division of Gastroenterology.
  • 14. Benioff Center for Microbiome Medicine, and.
  • 15. Division of Experimental Medicine, Department of Medicine, UCSF, San Francisco, USA.
  • 16. Department of Molecular and Cell Biology, University of California, Berkeley, USA.
  • 17. Department of Pathology, UCSF, San Francisco, USA.
PMID: 41746743 DOI: 10.1172/JCI200062
Abstract

Neonatal life is marked by rapid antigen exposure, necessitating establishment of peripheral immune tolerance via conversion of naive CD4+ T cells into Tregs. We demonstrated heightened capacity for FOXP3 expression and tolerogenic function among cord blood versus adult blood naive CD4+ T cells. Further, this was linked to a distinct cord blood metabolic profile and elevated neonatal expression of the NADase, CD38. Early-life naive CD4+ T cells demonstrated a metabolic preference for glycolysis, which directly facilitated their differentiation trajectory. We revealed an age-dependent gradient in CD38 levels on naive CD4+ T cells and showed that high CD38 expression contributes to the glycolytic state and tolerogenic potential of neonatal CD4+ T cells, effects mediated at least partly 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.

Keywords
Development; Immunology; Metabolism; T cell development; Tolerance; Tregs.
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