Histone lactylation drives CD8+ T cell metabolism and function
(1) Raychaudhuri D (2) Singh P (3) Chakraborty B (4) Hennessey M (5) Tannir AJ (6) Byregowda S (7) Natarajan SM (8) Trujillo-Ocampo A (9) Im JS (10) Goswami S
Raychaudhuri and Singh et al. evaluated both H3K9 and H3K18la histone lactylation in CD8+ T cells before and after T cell activation and found that they were generally associated with the initiation of transcription, though they marked different genes in different subsets. While H3K9 was enriched across subsets and appeared to be associated with the maintenance of mitochondrial metabolism in naive and memory T cells, H3K18la was induced by increased lactate production, was mainly enriched following T cell activation, and was associated with a shift towards glycolysis and enhanced effector functions. Interventions that enhanced glycolysis and subsequent lactylation could be used to enhance effector functions for immunotherapy.
(1) Raychaudhuri D (2) Singh P (3) Chakraborty B (4) Hennessey M (5) Tannir AJ (6) Byregowda S (7) Natarajan SM (8) Trujillo-Ocampo A (9) Im JS (10) Goswami S
Raychaudhuri and Singh et al. evaluated both H3K9 and H3K18la histone lactylation in CD8+ T cells before and after T cell activation and found that they were generally associated with the initiation of transcription, though they marked different genes in different subsets. While H3K9 was enriched across subsets and appeared to be associated with the maintenance of mitochondrial metabolism in naive and memory T cells, H3K18la was induced by increased lactate production, was mainly enriched following T cell activation, and was associated with a shift towards glycolysis and enhanced effector functions. Interventions that enhanced glycolysis and subsequent lactylation could be used to enhance effector functions for immunotherapy.
ABSTRACT: The activation and functional differentiation of CD8(+) T cells are linked to metabolic pathways that result in the production of lactate. Lactylation is a lactate-derived histone post-translational modification; however, the relevance of histone lactylation in the context of CD8(+) T cell activation and function is not known. Here, we show the enrichment of H3K18 lactylation (H3K18la) and H3K9 lactylation (H3K9la) in human and mouse CD8(+) T cells, which act as transcription initiators of key genes regulating CD8(+) T cell function. Further, we note distinct patterns of H3K18la and H3K9la in CD8(+) T cell subsets linked to their specific metabolic profiles. Additionally, we find that modulation of H3K18la and H3K9la by targeting metabolic and epigenetic pathways influence CD8(+) T cell effector function, including antitumor immunity, in preclinical models. Overall, our study uncovers the potential roles of H3K18la and H3K9la in CD8(+) T cells.
Author Info:
(1) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (2) Department of Immunology, The University of Texas MD Anderson Cancer Center,
Houston, TX, USA. (3) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (4) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (5) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (6) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (7) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (8) Department of Hematopoietic Biology and Malignancy, Division of Cancer Medicine, MD Anderson Cancer Center, Houston, TX, USA. (9) Department of Hematopoietic Biology and Malignancy, Division of Cancer Medicine, MD Anderson Cancer Center, Houston, TX, USA. The University of Texas MD Anderson Cancer Center, UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA. Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, MD Anderson Cancer Center, Houston, TX, USA. (10) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. sgoswami@mdanderson.org. Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. sgoswami@mdanderson.org. James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. sgoswami@mdanderson.org.
