biostudies-literatureBhatt BNIDDK NIH HHSNIAID NIH HHSNCI NIH HHSPaceline Award FundNational Institutes of HealthPaceline Award Fund 8471TNIH HHS446-459https://www.ebi.ac.uk/biostudies/studies/S-EPMC11952874biostudies-literatureUnknown214(3)In naïve mice, a fraction of CD8 T cells displaying high affinity for self-MHC peptide complexes develop into virtual memory T (TVM) cells. Due to self-reactivity, TVM cells are exposed to persistent antigenic stimulation, a condition known to induce T cell exhaustion. However, TVM cells do not exhibit characteristics similar to exhausted CD8 T (TEX) cells. Here, we tested the role of the UFL1, E3 ligase of the ufmylation pathway in TVM cells. We show that UFL1 prevents the acquisition of epigenetic, transcriptional, and phenotypic changes in TVM cells that are similar to TEX cells and thus promote their survival and function. UFL1-deficient TVM cells failed to protect mice against Listeria infection. Epigenetic analysis showed higher BATF activity in UFL1-deficient TVM cells. Deletion of Journal of immunology (Baltimore, Md. : 1950)UFL1 promotes survival and function of virtual memory CD8 T cells.PMC11952874R01 AI1557748471TR01 CA264983R01 CA276933R01AI155774R01 CA103320R01 CA062130R01 DK113409Li HAnazodo FMoskophidis DGanesan DRathakrishnan AZhu HPacholczyk RLokeshwar VBKumar KSingh NSheridan BSJiang CJayavelu TMunn DHBhatt BWanna AShi HfalseUFL1 promotes survival and function of virtual memory CD8 T cells.In naïve mice, a fraction of CD8 T cells displaying high affinity for self-MHC peptide complexes develop into virtual memory T (TVM) cells. Due to self-reactivity, TVM cells are exposed to persistent antigenic stimulation, a condition known to induce T cell exhaustion. However, TVM cells do not exhibit characteristics similar to exhausted CD8 T (TEX) cells. Here, we tested the role of the UFL1, E3 ligase of the ufmylation pathway in TVM cells. We show that UFL1 prevents the acquisition of epigenetic, transcriptional, and phenotypic changes in TVM cells that are similar to TEX cells and thus promote their survival and function. UFL1-deficient TVM cells failed to protect mice against Listeria infection. Epigenetic analysis showed higher BATF activity in UFL1-deficient TVM cells. Deletion of 2025-01-01T00:00:00Z2025 Mar2026-07-09T12:04:42.079Z2026-07-09T11:08:37.516ZS-EPMC119528744007309510.1093/jimmun/vkae042