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Abstract
We are witnessing a significant increase in complex T cell-mediated immune disorders, such as food allergies and autoimmune diseases, which are driven by diverse inflammatory pathways. This trend suggests that the activation threshold for T cells may be altered. Understanding how to modulate the activation threshold of T cells will have profound implications not only for the treatment of autoimmune disorders but also for cancer therapy. We demonstrate that the effector program of CD8⁺ T cells (including circulating 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, and, instead, has been shown to function as a scaffolding protein or to deacetylate non-histone targets. Using small interfering RNA (siRNA) in cell lines of primary human cytotoxic CD8⁺ intraepithelial lymphocytes (IELs), we show that the loss of HDAC5 decreases their effector function. Furthermore, inhibiting HDAC5 activity with the HDAC4/5 inhibitor LMK235 reduces the pathogenic reprogramming and effector potential of human ex vivo isolated intestinal IELs following IL-15 and TCR-mediated stimulation, while inhibition of HDAC4 does not. This result suggests that HDAC5 enzymatic activity may be important for promoting the activation of CD8⁺ IELs. Finally, our data indicate that HDAC5 inhibition broadly impacts CD8⁺ T cell activation, including in circulating memory and naïve CD8⁺ T cell subsets, and across multiple stimuli. Interestingly, HDAC5 promotes the effector program of CD8⁺ T cells following both conventional TCR-mediated activation, but also in settings of non-conventional cytokine-mediated activation, where the effect may even be stronger. Overall, this work identifies HDAC5 as a critical enzyme regulating the activation of CD8⁺ T cells, including within tissue environments. It also highlights the potential of targeting HDAC5 to modulate CD8⁺ T cell responses in inflammatory disorders and paves the way for novel therapeutic strategies aimed at adjusting T cell activation thresholds.