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ResearchIn-Press PreviewDevelopmentImmunologyMetabolism Open Access | 10.1172/JCI200062

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

Laura R. Dwyer,1 Andrea M. DeRogatis,2 Sean Clancy,2 Victoire Gouirand,2 Charles Chien,3 Elizabeth E. Rogers,4 Scott P. Oltman,4 Laura L. Jelliffe-Pawlowski,4 Theo van den Broek,5 Femke van Wijk,5 Susan V. Lynch,6 Rachel L. Rutishauser,7 Allon Wagner,3 Alexis J. Combes,8 and Tiffany C. Scharschmidt2

1Biomedical Sciences Graduate Program, UCSF, San Francisco, United States of America

2Department of Dermatology, UCSF, San Francisco, United States of America

3Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

4Healthy Outcomes of Pregnancy for Everyone Research Consortium, UCSF, San Francisco, United States of America

5Center for Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, Netherlands

6Division of Gastroenterology, Department of Medicine, UCSF, San Francisco, United States of America

7Division of Experimental Medicine, Department of Medicine, UCSF, San Francisco, United States of America

8Department of Pathology, UCSF, San Francisco, United States of America

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1Biomedical Sciences Graduate Program, UCSF, San Francisco, United States of America

2Department of Dermatology, UCSF, San Francisco, United States of America

3Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

4Healthy Outcomes of Pregnancy for Everyone Research Consortium, UCSF, San Francisco, United States of America

5Center for Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, Netherlands

6Division of Gastroenterology, Department of Medicine, UCSF, San Francisco, United States of America

7Division of Experimental Medicine, Department of Medicine, UCSF, San Francisco, United States of America

8Department of Pathology, UCSF, San Francisco, United States of America

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1Biomedical Sciences Graduate Program, UCSF, San Francisco, United States of America

2Department of Dermatology, UCSF, San Francisco, United States of America

3Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

4Healthy Outcomes of Pregnancy for Everyone Research Consortium, UCSF, San Francisco, United States of America

5Center for Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, Netherlands

6Division of Gastroenterology, Department of Medicine, UCSF, San Francisco, United States of America

7Division of Experimental Medicine, Department of Medicine, UCSF, San Francisco, United States of America

8Department of Pathology, UCSF, San Francisco, United States of America

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1Biomedical Sciences Graduate Program, UCSF, San Francisco, United States of America

2Department of Dermatology, UCSF, San Francisco, United States of America

3Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

4Healthy Outcomes of Pregnancy for Everyone Research Consortium, UCSF, San Francisco, United States of America

5Center for Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, Netherlands

6Division of Gastroenterology, Department of Medicine, UCSF, San Francisco, United States of America

7Division of Experimental Medicine, Department of Medicine, UCSF, San Francisco, United States of America

8Department of Pathology, UCSF, San Francisco, United States of America

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1Biomedical Sciences Graduate Program, UCSF, San Francisco, United States of America

2Department of Dermatology, UCSF, San Francisco, United States of America

3Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

4Healthy Outcomes of Pregnancy for Everyone Research Consortium, UCSF, San Francisco, United States of America

5Center for Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, Netherlands

6Division of Gastroenterology, Department of Medicine, UCSF, San Francisco, United States of America

7Division of Experimental Medicine, Department of Medicine, UCSF, San Francisco, United States of America

8Department of Pathology, UCSF, San Francisco, United States of America

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1Biomedical Sciences Graduate Program, UCSF, San Francisco, United States of America

2Department of Dermatology, UCSF, San Francisco, United States of America

3Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

4Healthy Outcomes of Pregnancy for Everyone Research Consortium, UCSF, San Francisco, United States of America

5Center for Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, Netherlands

6Division of Gastroenterology, Department of Medicine, UCSF, San Francisco, United States of America

7Division of Experimental Medicine, Department of Medicine, UCSF, San Francisco, United States of America

8Department of Pathology, UCSF, San Francisco, United States of America

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1Biomedical Sciences Graduate Program, UCSF, San Francisco, United States of America

2Department of Dermatology, UCSF, San Francisco, United States of America

3Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

4Healthy Outcomes of Pregnancy for Everyone Research Consortium, UCSF, San Francisco, United States of America

5Center for Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, Netherlands

6Division of Gastroenterology, Department of Medicine, UCSF, San Francisco, United States of America

7Division of Experimental Medicine, Department of Medicine, UCSF, San Francisco, United States of America

8Department of Pathology, UCSF, San Francisco, United States of America

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1Biomedical Sciences Graduate Program, UCSF, San Francisco, United States of America

2Department of Dermatology, UCSF, San Francisco, United States of America

3Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

4Healthy Outcomes of Pregnancy for Everyone Research Consortium, UCSF, San Francisco, United States of America

5Center for Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, Netherlands

6Division of Gastroenterology, Department of Medicine, UCSF, San Francisco, United States of America

7Division of Experimental Medicine, Department of Medicine, UCSF, San Francisco, United States of America

8Department of Pathology, UCSF, San Francisco, United States of America

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1Biomedical Sciences Graduate Program, UCSF, San Francisco, United States of America

2Department of Dermatology, UCSF, San Francisco, United States of America

3Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

4Healthy Outcomes of Pregnancy for Everyone Research Consortium, UCSF, San Francisco, United States of America

5Center for Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, Netherlands

6Division of Gastroenterology, Department of Medicine, UCSF, San Francisco, United States of America

7Division of Experimental Medicine, Department of Medicine, UCSF, San Francisco, United States of America

8Department of Pathology, UCSF, San Francisco, United States of America

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1Biomedical Sciences Graduate Program, UCSF, San Francisco, United States of America

2Department of Dermatology, UCSF, San Francisco, United States of America

3Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

4Healthy Outcomes of Pregnancy for Everyone Research Consortium, UCSF, San Francisco, United States of America

5Center for Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, Netherlands

6Division of Gastroenterology, Department of Medicine, UCSF, San Francisco, United States of America

7Division of Experimental Medicine, Department of Medicine, UCSF, San Francisco, United States of America

8Department of Pathology, UCSF, San Francisco, United States of America

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1Biomedical Sciences Graduate Program, UCSF, San Francisco, United States of America

2Department of Dermatology, UCSF, San Francisco, United States of America

3Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

4Healthy Outcomes of Pregnancy for Everyone Research Consortium, UCSF, San Francisco, United States of America

5Center for Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, Netherlands

6Division of Gastroenterology, Department of Medicine, UCSF, San Francisco, United States of America

7Division of Experimental Medicine, Department of Medicine, UCSF, San Francisco, United States of America

8Department of Pathology, UCSF, San Francisco, United States of America

Find articles by Lynch, S. in: PubMed | Google Scholar

1Biomedical Sciences Graduate Program, UCSF, San Francisco, United States of America

2Department of Dermatology, UCSF, San Francisco, United States of America

3Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

4Healthy Outcomes of Pregnancy for Everyone Research Consortium, UCSF, San Francisco, United States of America

5Center for Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, Netherlands

6Division of Gastroenterology, Department of Medicine, UCSF, San Francisco, United States of America

7Division of Experimental Medicine, Department of Medicine, UCSF, San Francisco, United States of America

8Department of Pathology, UCSF, San Francisco, United States of America

Find articles by Rutishauser, R. in: PubMed | Google Scholar |

1Biomedical Sciences Graduate Program, UCSF, San Francisco, United States of America

2Department of Dermatology, UCSF, San Francisco, United States of America

3Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

4Healthy Outcomes of Pregnancy for Everyone Research Consortium, UCSF, San Francisco, United States of America

5Center for Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, Netherlands

6Division of Gastroenterology, Department of Medicine, UCSF, San Francisco, United States of America

7Division of Experimental Medicine, Department of Medicine, UCSF, San Francisco, United States of America

8Department of Pathology, UCSF, San Francisco, United States of America

Find articles by Wagner, A. in: PubMed | Google Scholar |

1Biomedical Sciences Graduate Program, UCSF, San Francisco, United States of America

2Department of Dermatology, UCSF, San Francisco, United States of America

3Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

4Healthy Outcomes of Pregnancy for Everyone Research Consortium, UCSF, San Francisco, United States of America

5Center for Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, Netherlands

6Division of Gastroenterology, Department of Medicine, UCSF, San Francisco, United States of America

7Division of Experimental Medicine, Department of Medicine, UCSF, San Francisco, United States of America

8Department of Pathology, UCSF, San Francisco, United States of America

Find articles by Combes, A. in: PubMed | Google Scholar |

1Biomedical Sciences Graduate Program, UCSF, San Francisco, United States of America

2Department of Dermatology, UCSF, San Francisco, United States of America

3Department of Electrical Engineering and Computer Sciences, UC Berkeley, Berkeley, United States of America

4Healthy Outcomes of Pregnancy for Everyone Research Consortium, UCSF, San Francisco, United States of America

5Center for Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, Netherlands

6Division of Gastroenterology, Department of Medicine, UCSF, San Francisco, United States of America

7Division of Experimental Medicine, Department of Medicine, UCSF, San Francisco, United States of America

8Department of Pathology, UCSF, San Francisco, United States of America

Find articles by Scharschmidt, T. in: PubMed | Google Scholar |

Published February 26, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI200062.
Copyright © 2026, Dwyer et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published February 26, 2026 - Version history
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Abstract

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.

Graphical Abstract
graphical abstract
Supplemental material

View Table S1: CB and AB raw gene counts

View Table S2: CB and AB DEGs within group over time

View Table S3: CB vs. AB DEGs by timepoint

View

View Table S4: Antibody List

Version history
  • Version 1 (February 26, 2026): In-Press Preview
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