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

Adaptive immunity requires the expansion of high affinity lymphocytes from a heterogenous pool. While current models explain this through signal transduction, we hypothesized that antigen affinity tunes discrete metabolic pathways to license clonal lymphocyte dynamics. Herein we identify NAD biosynthesis as a biochemical hub for the TCR affinity-dependent metabolome. Through its’ central anabolic role, NAD biosynthesis governs a quiescence exit checkpoint, pacing proliferation. Normalizing cellular NAD(H) likewise normalizes proliferation across affinities and enhancing NAD biosynthesis permits expansion of lower affinity clones. Furthermore, single-cell differences in NAD(H) predict division potential for both T- and B-cells, prior to the first division, unmixing proliferative heterogeneity. We believe this supports a broader paradigm in which complex signaling networks converge on metabolic pathways to control single-cell behavior.

Author dc:creator

• Turner, Lucien, Harris

Advisor dc:contributor.advisor

• Bailis, Will

• Immunology and Infectious Disease

Language dc:language.iso

en

Repository record dc:identifier.uri

https://repository.upenn.edu/handle/20.500.14332/60040

OAI identifier oai:identifier

oai:repository.upenn.edu:20.500.14332/60040