Transcriptional control of T cell tissue adaptation and effector function in infants and adults

Szabo, P. A.; Levitin, H. M.; Connors, T. J.; Chen, D.; Jin, J.; Thapa, P.; Guyer, R.; Caron, D. P.; Gray, J. I.; Matsumoto, R.; Kubota, M.; Brusko, M.; Brusko, T. M.; Farber, D. L.; Sims, P. A.

doi:10.1101/2025.02.01.636039

bioRxiv · 10.1101/2025.02.01.636039

Transcriptional control of T cell tissue adaptation and effector function in infants and adults

Szabo, P. A.·Levitin, H. M.·Connors, T. J.·Chen, D.·Jin, J.·Thapa, P.·Guyer, R.·Caron, D. P.·Gray, J. I.·Matsumoto, R.·Kubota, M.·Brusko, M.·Brusko, T. M.·Farber, D. L.·Sims, P. A.

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Abstract

The first years of life are essential for the development of memory T cells, which rapidly populate the bodys diverse tissue sites during infancy. However, the degree to which tissue memory T cell responses in early life reflect those during adulthood is unclear. Here, we use single cell RNA-sequencing of resting and ex vivo activated T cells from lymphoid and mucosal tissues of infant (aged 2-9 months) and adult (aged 40-65 years) human organ donors to dissect the transcriptional programming of memory T cells over age. Infant memory T cells demonstrate a unique stem-like transcriptional profile and tissue adaptation program, yet exhibit reduced activation capacity and effector function relative to adults. Using CRISPR-Cas9 knockdown, we define Helios (IKZF2) as a critical transcriptional regulator of the infant-specific tissue adaptation program and restricted effector state. Our findings reveal key transcriptional mechanisms that control tissue T cell fate and function in early life.

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Szabo, P. A., Levitin, H. M., Connors, T. J., Chen, D., Jin, J., Thapa, P., Guyer, R., Caron, D. P., Gray, J. I., Matsumoto, R., Kubota, M., Brusko, M., Brusko, T. M., Farber, D. L., Sims, P. A.. 2025-02-06. Transcriptional control of T cell tissue adaptation and effector function in infants and adults. https://doi.org/10.1101/2025.02.01.636039

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