Nutrient-sensitive histone propionylation regulates T cell fate and function

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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BibTeX RIS

BibTeX

@misc{jaccard2026nutrientsensitive,
  title = {{Nutrient-sensitive histone propionylation regulates T cell fate and function}},
  author = {A. Jaccard and K. Rome and Q. Yang and S. Zhang and N. Ford and A. Chatoff and T. N. Van Le and M. Noji and A. Andress Huacachino and S. Stransky Lauar and C. Pondevida and K. Trihemasava and L. V. Pinheiro and S. Bhadsalve and E. K. Ko and C. Salinas and M. M. Marcinkiewicz and B. C. Capell and G. Vahedi and S. Sidoli and R. S. OConnor and W. Bailis and N. W. Snyder and K. E. Wellen},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.01.756002},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.01.756002v1},
  note = {CC BY-NC},
}

RIS

TY  - UNPB
TI  - Nutrient-sensitive histone propionylation regulates T cell fate and function
AU  - A. Jaccard
AU  - K. Rome
AU  - Q. Yang
AU  - S. Zhang
AU  - N. Ford
AU  - A. Chatoff
AU  - T. N. Van Le
AU  - M. Noji
AU  - A. Andress Huacachino
AU  - S. Stransky Lauar
AU  - C. Pondevida
AU  - K. Trihemasava
AU  - L. V. Pinheiro
AU  - S. Bhadsalve
AU  - E. K. Ko
AU  - C. Salinas
AU  - M. M. Marcinkiewicz
AU  - B. C. Capell
AU  - G. Vahedi
AU  - S. Sidoli
AU  - R. S. OConnor
AU  - W. Bailis
AU  - N. W. Snyder
AU  - K. E. Wellen
PY  - 2026
DA  - 2026/10/01
PB  - bioRxiv
DO  - 10.64898/2026.10.01.756002
UR  - https://www.biorxiv.org/content/10.64898/2026.10.01.756002v1
AB  - 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.
ER  -

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