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 2

Transcriptomic data analysis and in silico modeling of CB versus AB naive CD4+ T cells reveal unique functional and metabolic programs.

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Transcriptomic data analysis and in silico modeling of CB versus AB naiv...
(A) PCA of bulk RNA-seq data from naive CD4+ T cells (CD4+CD8negCD45RA+CD27+CCR7+CD95neg) sorted from CB and AB. Samples taken 0, 3, 24, and 48 hours after stimulation. (B) Heatmap of top variable features (i.e., gene clusters). (C) Mapping of cluster expression over time. Black dots show mean z-score of cluster genes per point. Colors correspond with clusters in B. (D) Volcano plots of differential gene expression for CB versus AB naive CD4+ T cells at each time point, with specific genes related to tolerance or activated effector cells highlighted. Horizontal dotted line: Benjamini-Hochberg–adjusted P of 0.05. (E) Normalized CD38 gene counts. (F) Differential expression of key metabolic genes in scRNA-seq dataset from Bunis et al. (5). (G) Compass comparison of CB versus AB naive CD4+ T cell metabolic states in central carbon metabolism, with glycolysis reactions as annotated in the Human1 GEM at left (up in CB) and downregulated OXPHOS reactions at right (up in AB). In E, horizontal bars depict mean values, with unpaired t test used and ***P ≤ 0.001.