Distinct transcription factors control tissue adaptation and effector function in infant and adult memory T cells

Early life is essential for establishing memory T cells, which rapidly populate mucosal sites during infancy, although these nascent memory T cells are less protective than their adult counterparts. Here we used single-cell RNA sequencing of resting and CD3+CD28 antibody-stimulated T cells from lymphoid and mucosal tissues of infant (2-9 months) and adult (40-63 years) organ donors to investigate age-dependent mechanisms for functional regulation of human memory T cells. Infant CCL5⁺ effector memory T cells exhibited reduced effector function compared to adults. Transcription factor network analysis identified HELIOS and KLF6 as regulators of memory T cell states in infant and adult tissues, respectively. Using single-nucleus RNA sequencing, assay for transposase-accessible chromatin sequencing and CRISPR-Cas9 knockout, we defined HELIOS (IKZF2) as a critical regulator of the infant-specific transcriptional program in CCL5⁺ effector memory T cells and restricted effector function in SELL⁺CCR7⁺ naive and/or central memory T cells. Our findings reveal key mechanisms controlling T cell functional states in early life.