You're (Cyto)Toxic: HDAC5 controls the activation of cytotoxic CD8⁺ intraepithelial lymphocytes

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B701
Abstract ID: 4684

Presenting Author:
Megan Borregard , PhD Student at Univ. of Chicago

Abstract:

In Celiac Disease, upregulation of IL-15 by distressed intestinal epithelial cells results in the pathogenic reprogramming of cytotoxic CD8+ intraepithelial lymphocytes (IE-CTLs), which then promote tissue destruction. We found that IL-15 induced major transcriptional changes associated with effector function in IE-CTLs, but did so without impacting chromatin accessibility. Here, we explore how the intestinal microenvironment controls IL-15-mediated activation of IE-CTLs without restructuring their epigenetic landscape. We found that butyrate, a known immunomodulatory molecule, reduced expression of Granzyme B and NKG2D in ex vivo human IE-CTLs. Further, butyrate broadly impacted the expression of genes linked to survival and activation in a histone deacetylase (HDAC)-dependent manner. Using small interfering RNA, we determined that HDAC5 controlled the IL-15-mediated activation of IE-CTLs without impacting their survival. HDAC5 has little to no deacetylase activity against histone tails, and our data suggest that it remains localized in the cytoplasm following stimulation. We believe that HDAC5 may deacetylate key signaling molecules to promote their activation, and thus regulate the IL-15-mediated licensing of IE-CTLs. Understanding how HDAC5 controls activation of IE-CTLs could shed light on novel therapeutic options that specifically target IE-CTL activation responses in inflammatory T cell disorders, like Celiac Disease, without impacting their survival in the tissue.