Methionine metabolism shapes epigenetic and functional programs of developing CD8+ T cells

Introduction/Rationale: Host defense evolves across the lifespan, with newborns and infants exhibiting distinct susceptibilities to infection compared to older children and adults. Neonatal CD8+ T cells exhibit distinct transcriptional and functional states, favoring effector differentiation over memory formation. These developmental differences arise from epigenetic regulation of chromatin accessibility and transcription factor networks governing effector, memory, and exhaustion programs. Our preliminary data identify methionine metabolism as a key regulator of these programs. Methionine-derived S-adenosylmethionine (SAM) fuels histone methylation and other transmethylation reactions; increased methionine utilization in neonatal cells may support these epigenetic circuits, whereas its restriction impairs activation, proliferation, and effector differentiation.

Methods: To dissect developmental regulation of T cell function, we integrated RNA sequencing, CUT&RUN profiling, and cellular immunology of activated cells to define age-specific transcriptional and chromatin landscapes. Targeted metabolomics quantified nutrient utilization, and CRISPR-Cas9 knockouts identified transcriptional regulators driving developmental divergence.

Results: Methionine emerged as one of the most differentially regulated pathways, with neonatal cells expressing higher levels of histone methyltransferases and demethylases. They also deposit activating H3K4 methylation marks at Ikzf2 (Helios) and Eomes loci. Helios expression was higher in neonatal cells and was rescued by SAM under methionine restriction. Functional assays demonstrated neonatal dependence on methionine for survival, proliferation and memory formation. Isotope tracing further showed faster methionine turnover in neonatal cells.

Conclusion: Together, these findings suggest a methionine-dependent epigenetic regulation as a mechanism driving early-life T cell responses and propose metabolic interventions to enhance immunity and optimize T cell–based therapies in infancy.