HDAC5 regulates the activation of cytotoxic CD8+ T cells 4190

Abstract Description We are witnessing a significant increase in complex T cell-mediated immune disorders, such as food allergies and autoimmune disease. This trend suggests that the activation threshold for T cells may be altered, and understanding how to modulate this threshold has profound implications for disease treatment. In this study, we demonstrate that the effector program of CD8? T cells (including naïve, circulating memory, and tissue-resident cells) induced by TCR and cytokine stimulation is regulated by the class II histone deacetylase, HDAC5. HDAC5 exhibits little to no deacetylase activity against histone tails, but can function in the cytoplasm as a scaffolding protein or to directly deacetylate protein targets. Using small interfering RNA (siRNA) in cell lines of primary human CD8+ cytotoxic intraepithelial lymphocytes (IE-CTLs), we show that the loss of HDAC5 decreases their activation. Furthermore, inhibiting HDAC5 activity with the HDAC4/5 inhibitor LMK235 reduces the activation potential of ex vivo isolated human intestinal IE-CTLs following stimulation, suggesting that HDAC5 enzymatic activity is required for this effect. Finally, our data indicate that HDAC5 inhibition broadly impacts CD8? T cell activation, including in circulating memory and naïve subsets. This work identifies HDAC5 as a critical enzyme regulating the activation of CD8? T cells and highlights the potential of targeting HDAC5 to modulate CD8? T cell activation thresholds in inflammatory disorders. Funding Sources Supported by NIH BIBIB 2 T32 EB 9412; NSF Graduate Research Fellowship Program; University of Chicago Celiac Disease Research Center. Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)