2. Academic Validation
  3. CD38 expression by neonatal human naive CD4+ T cells shapes their distinct metabolic and tolerogenic properties

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

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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