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 1

CD38 expression is highly enriched on naive early-life CD4+ T cells.

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CD38 expression is highly enriched on naive early-life CD4+ T cells. (A)...
(A) MFI of surface CD38 by flow cytometry on CD3+ and CD3- cells from nonactivated peripheral CB and AB. CD38 MFI on (B) various immune cell populations and (C) CD4+ T cell subsets. (D) Pattern of CD38 surface staining on naive CD4+ T cells from CB and AB. (E) CD38 MFI on naive CD4+ T cells from CB, peripheral blood from 6-week-old preterm infants, or AB. (F) CD38 MFI on naive CD4+ T cells from peripheral blood from healthy pediatric donors. Data originally generated for van den Broek et al. (28). (G) CD38 and CD31 expression on nonactivated naive CD4+ T cells from CB and AB and the CD38 expression pattern on CD31+ versus CD31– cells by age. (B–D and G) One of 2 representative experiments. (E and F) Performed once. Horizontal bars depict mean values in each graph. Two-way ANOVA with multiple comparisons used. *P ≤ 0.05, **P ≤ 0.02, ***P ≤ 0.001, ****P < 0.0001.