Nutrient-sensitive histone propionylation regulates T cell fate and function

Jaccard, A.; Rome, K.; Yang, Q.; Zhang, S.; Ford, N.; Chatoff, A.; Van Le, T. N.; Noji, M.; Andress Huacachino, A.; Stransky Lauar, S.; Pondevida, C.; Trihemasava, K.; Pinheiro, L. V.; Bhadsalve, S.; Ko, E. K.; Salinas, C.; Marcinkiewicz, M. M.; Capell, B. C.; Vahedi, G.; Sidoli, S.; OConnor, R. S.; Bailis, W.; Snyder, N. W.; Wellen, K. E.

doi:10.64898/2026.10.01.756002

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bioRxiv · 10.64898/2026.10.01.756002

Nutrient-sensitive histone propionylation regulates T cell fate and function

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Abstract

Tissue microenvironments differ widely in nutrient composition; yet how local nutrient conditions shape epigenetic programs that direct immune cell fate is poorly understood. We identify histone lysine propionylation (Kpr) as a chromatin mechanism linking nutrient availability to T cell fate decisions. Proteomic analysis reveals that Kpr is broadly reduced in exhausted T cells. H3K18pr is enriched at stemness-associated loci in effector T cells and depleted upon exhaustion. Isoleucine and propionate supply propionyl-CoA in T cells, and restricted nutrient availability within the tumor microenvironment limits histone Kpr, promoting T cell exhaustion. Disrupting isoleucine catabolism in T cells further suppresses Kpr, without altering histone acetylation, and impairs T cell function and antitumor immunity in a manner rescued by propionate. Dietary supplementation of isoleucine and propionate increases Kpr in tumor infiltrating lymphocytes, limits exhaustion, and improves tumor control. These findings establish a microenvironment-chromatin axis crucial for antitumor immunity and amenable to nutritional intervention.

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Jaccard, A., Rome, K., Yang, Q., Zhang, S., Ford, N., Chatoff, A., Van Le, T. N., Noji, M., Andress Huacachino, A., Stransky Lauar, S., Pondevida, C., Trihemasava, K., Pinheiro, L. V., Bhadsalve, S., Ko, E. K., Salinas, C., Marcinkiewicz, M. M., Capell, B. C., Vahedi, G., Sidoli, S., OConnor, R. S., Bailis, W., Snyder, N. W., Wellen, K. E.. 2026-10-06. Nutrient-sensitive histone propionylation regulates T cell fate and function. https://doi.org/10.64898/2026.10.01.756002

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