CD38 expression by neonatal human naïve CD4+ T cells shapes their distinct metabolic and tolerogenic properties
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 demonstrated heightened capacity for FOXP3 expression and tolerogenic function among cord blood versus adult blood naive CD4+ T cells and showed that this is linked to their unique metabolic profile and elevated expression of the NADase, CD38. Early-life naïve 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 naïve CD4+ T cells and showed that high CD38 expression contributes to both the glycolytic state and tolerogenic potential of neonatal CD4+ T cells, effects that were 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.
Authors
- Laura R. Dwyer (ORCID: https://orcid.org/0000-0002-5689-2541)
- Sean Clancy
- Rachel L. Rutishauser (ORCID: https://orcid.org/0000-0003-3596-059X)
- Scott P. Oltman (ORCID: https://orcid.org/0000-0002-6560-3334)
- Tiffany C. Scharschmidt (ORCID: https://orcid.org/0000-0001-5517-089X)
- Victoire Gouirand (ORCID: https://orcid.org/0000-0002-2666-0061)
- Alexis J. Combes (ORCID: https://orcid.org/0000-0002-9110-6542)
- Elizabeth E. Rogers (ORCID: https://orcid.org/0000-0001-5449-9693)
- Laura L. Jelliffe‐Pawlowski (ORCID: https://orcid.org/0000-0001-6258-648X)
- Allon Wagner
- Theo van den Broek
- Andrea M. DeRogatis
- Charles Chien
- Susan V. Lynch
- Femke van Wijk
Institutions
- Berkeley College (US)
- Outcomes Research Consortium (US)
- University of California, San Francisco (US)
- Utrecht University (NL)
- University Medical Center Utrecht (NL)
- University of California San Francisco Medical Center (US)
- University of San Francisco (US)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2026-02-26
- DOI
- https://doi.org/10.1172/jci200062
- Primary Topic
- Calcium signaling and nucleotide metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Institutes of Health
- University of California, San Francisco