2. Academic Validation
  3. Single-cell NAD(H) levels predict clonal lymphocyte expansion dynamics

Single-cell NAD(H) levels predict clonal lymphocyte expansion dynamics

  • Sci Immunol. 2024 Mar 15;9(93):eadj7238. doi: 10.1126/sciimmunol.adj7238.
Lucien Turner 1,  Tran Ngoc Van Le 1,  Eric Cross 1 2,  Clemence Queriault 1,  Montana Knight 1 3,  Krittin Trihemasava 1,  James Davis 4,  Patrick Schaefer 5,  Janet Nguyen 1,  Jimmy Xu 6,  Brian Goldspiel 1,  Elise Hall 1,  Kelly Rome 1,  Michael Scaglione 1,  Joel Eggert 7,  Byron Au-Yeung 7,  Douglas C Wallace 5 8,  Clementina Mesaros 6,  Joseph A Baur 4,  Will Bailis 1 2
Affiliations

Affiliations

  • 1 Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 2 Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 3 Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 4 Department of Physiology and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 5 Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 6 Center of Excellence in Environmental Toxicology and Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 7 Division of Immunology, Lowance Center for Human Immunology, Department of Medicine, Emory University, Atlanta, GA 30322, USA.
  • 8 Department of Pediatrics, Division of Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
PMID: 38489349 DOI: 10.1126/sciimmunol.adj7238
Abstract

Adaptive immunity requires the expansion of high-affinity lymphocytes from a heterogeneous pool. Whereas current models explain this through signal transduction, we hypothesized that antigen affinity tunes discrete metabolic pathways to license clonal lymphocyte dynamics. Here, we identify nicotinamide adenine dinucleotide (NAD) biosynthesis as a biochemical hub for the T cell receptor affinity-dependent metabolome. Through this central anabolic role, we found that NAD biosynthesis governs a quiescence exit checkpoint, thereby pacing proliferation. Normalizing cellular NAD(H) likewise normalizes proliferation across affinities, and enhancing NAD biosynthesis permits the expansion of lower affinity clones. Furthermore, single-cell differences in NAD(H) could predict division potential for both T and B cells, before the first division, unmixing proliferative heterogeneity. We believe that this supports a broader paradigm in which complex signaling networks converge on metabolic pathways to control single-cell behavior.

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