Kdm6b regulates the generation of effector CD8+ T cells by inducing chromatin accessibility in effector-associated genes

• Published in: The Journal of immunology (1950) Vol. 206; no. 1_Supplement; pp. 98 - 98.19
• Main Authors: Xu, Tianhao, Schutte, Alexander, Jimenez, Leandro, Gonçalves, Andre N.A., Keller, Ashleigh, Pipkin, Matthew E., Nakaya, Helder, Pereira, Renata M., Martinez, Gustavo J.
• Format: Journal Article
• Language: English
• Published: 01-05-2021
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.206.Supp.98.19

The transcriptional and epigenetic regulation of CD8+ T cell differentiation is critical for balancing pathogen eradication and long-term immunity by effector and memory CTLs respectively. Here, we demonstrate that the Lysine Demethylase 6b (Kdm6b) is essential for the proper generation and function of effector CD8+ T cells during acute infection and tumor eradication. We found that cells lacking Kdm6b (by either T cell-specific KO mice or knockdown utilizing shRNA strategies) show an enhanced generation of memory precursor and early effector cells upon acute viral infection in a cell-intrinsic manner. We also demonstrate that Kdm6b is indispensable for proper effector functions and tumor protection, and that memory CD8+ T cells lacking Kdm6b displayed a defective recall response. Mechanistically, we identified that Kdm6b, through induction of chromatin accessibility in key effector-associated gene loci, allows for the proper generation of effector CTLs. Our results pinpoint the essential function of Kdm6b in allowing chromatin accessibility in effector-associated genes, and identify Kdm6b as a potential target for therapeutics in diseases with dysregulated effector responses.