The roles of individual histone deacetylases in the regulation of T-cell development and function remain largely unknown. Here we provide evidence for HDAC11 as an epigenetic regulator of T-cell inflammatory response as well as CTL central memory formation. To investigate the role of HDAC11 in T-cells, an HDAC11 knockout (HDAC11KO) mouse model was utilized. HDAC11KO mice display no gross phenotypic abnormalities and no alterations in T-cell development or CD4+/CD8+ population distributions. However, HDAC11KO CTLs are hyper-proliferative and secrete significantly higher levels of IL-2, TNF, and IFN-γ upon activation, and HDAC11KO mice accumulate higher percentages of central memory CTLs. In an allogeneic bone marrow transfer model, HDAC11KO T-cells mediate more potent and robust graft vs host disease associated with increased inflammatory cytokines. Mechanistically, we provide evidence that in CTLs HDAC11 interacts with the Eomes gene promoter, a known regulator of IFN-γ production and memory formation. HDAC11KO CTLs, at both basal state and post stimulation, display higher levels of acetylation at the Eomes promoter, indicative of a permissive transcriptional state. Correspondingly, eomes mRNA levels in HDAC11KO cells are elevated. Finally, chromatin immunoprecipitation of HDAC11 reveals interaction between HDAC11 and the Eomes promoter in CTLs. These results support HDAC11 as an epigenetic regulator of CTL function and memory formation through epigenetic regulation of Eomes.
- Copyright © 2013 by The American Association of Immunologists, Inc.