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 6

Inhibition of CD38 activity in cord blood naive CD4+ T cells reduces their FOXP3 expression and glycolytic capacity.

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Inhibition of CD38 activity in cord blood naive CD4+ T cells reduces the...
(A) ECAR and (B) percent ATP from glycolysis in vehicle (DMSO) and CD38 inhibitor (5 μM 78c) CB naive CD4+ T cells. (C–E) Representative flow plots and graphs of percentage CD25+ cells and their FOXP3 MFI after 96 hours of stimulation under No Cytokine or IL-2+TGF-β conditions, where cells were treated with DMSO or 78c before and during activation. (F and G) ELISA-based measurement of cytokines in culture supernatant of DMSO- or 78c-treated CB No Cytokine cultures. (H) Treg stability assay following No Cytokine or IL-2+TGF-β culture with 78c or DMSO added before and during initial activation. Percentage CD25+ cells and their FOXP3 MFI for each condition. Data points represent individual donors. (A–E) One representative experiment from ≥ 2 repeats. (F–H) Performed once. Paired t tests used for A, B, and D–G and 2-way ANOVA with multiple comparisons used for H. *P ≤ 0.05, **P ≤ 0.02, ***P ≤ 0.001, ****P < 0.0001. Column heights in H depict mean value.