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SIKs regulate HDAC7 stabilization and cytokine recall in late-stage T cell effector differentiation

ABSTRACT: Understanding the mechanisms underlying the acquisition and maintenance of effector function during T cell differentiation is important to unraveling how these processes can be dysregulated in the context of disease and manipulated for therapeutic intervention. Herein, we report the identification of a novel regulator of murine T cell differentiation through the evaluation of a previously unreported activity of the kinase inhibitor, BioE-1197. Specifically, we demonstrate liver kinase B1 (LKB1) mediated activation of salt-inducible kinases (SIKs) epigenetically regulates cytokine recall potential in effector CD8+ and Th1 cells. Evaluation of this phenotype revealed SIK mediated phosphorylation dependent stabilization of histone deacetylase 7 (HDAC7) occurred during late-stage effector differentiation. HDAC7 stabilization increased nuclear HDAC7 levels which correlated with both global and cytokine loci specific reductions in the activating transcription mark, histone 3 lysine 27 acetylation (H3K27Ac). Accordingly, HDAC7 stabilization diminished transcriptional induction of cytokine upon re-stimulation. Inhibition of this pathway during differentiation produced effector T cells epigenetically poised for enhanced cytokine recall. This work identifies a novel target for enhancing effector T cell functionality.

ORGANISM(S): Mus musculus

PROVIDER: GSE242482 | GEO | 2023/09/12

REPOSITORIES: GEO

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SIKs regulate HDAC7 stabilization and cytokine recall in late-stage T cell effector differentiation

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