CD38 expression by neonatal human naive CD4+ T cells shapes their distinct metabolic and tolerogenic properties
Laura R. Dwyer, Andrea M. DeRogatis, Sean Clancy, Victoire Gouirand, Charles Chien, Elizabeth E. Rogers, Scott P. Oltman, Laura L. Jelliffe-Pawlowski, Theo van den Broek, Femke van Wijk, Susan V. Lynch, Rachel L. Rutishauser, Allon Wagner, Alexis J. Combes, Tiffany C. Scharschmidt
Laura R. Dwyer, Andrea M. DeRogatis, Sean Clancy, Victoire Gouirand, Charles Chien, Elizabeth E. Rogers, Scott P. Oltman, Laura L. Jelliffe-Pawlowski, Theo van den Broek, Femke van Wijk, Susan V. Lynch, Rachel L. Rutishauser, Allon Wagner, Alexis J. Combes, Tiffany C. Scharschmidt
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Research Article Development Immunology Metabolism

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

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.

Authors

Laura R. Dwyer, Andrea M. DeRogatis, Sean Clancy, Victoire Gouirand, Charles Chien, Elizabeth E. Rogers, Scott P. Oltman, Laura L. Jelliffe-Pawlowski, Theo van den Broek, Femke van Wijk, Susan V. Lynch, Rachel L. Rutishauser, Allon Wagner, Alexis J. Combes, Tiffany C. Scharschmidt

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Figure 7

The NAD+-dependent deacetylase, SIRT1, modulates FOXP3 expression in stimulated neonatal naive CD4+ T cells.

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The NAD+-dependent deacetylase, SIRT1, modulates FOXP3 expression in sti...
(A) Working model of CD38-NAD-SIRT1-Tregs-PPARγ interactions with pharmacological perturbations noted. (B and C) NAD+ levels in CB and AB naive CD4+ T cells (B) and DMSO- or 78c-treated CB naive CD4+ T cells (C). (D) FOXP3 acetylation in CB and AB naive CD4+ T cells via proximity ligation assay (PLA). (E–G) CD25+ percentage and FOXP3 MFI among CB and AB naive CD4+ T cells treated with DMSO (vehicle), SIRT1 activator, or SIRT1 inhibitor (E and F) or vehicle, CD38 inhibitor, SIRT1 inhibitor, or both (G) before activation under No Cytokine or IL-2+TGF-β conditions. Data points represent individual donors. B–F show 1 of 2 experimental replicates. G was performed once. Unpaired t test was used for B and D and paired t test for C. Two-way ANOVA with multiple comparisons used for E–G. *P ≤ 0.05, **P ≤ 0.02, ***P ≤ 0.001, ****P < 0.0001. Horizontal bars in B and D and column heights in E–G depict mean values.