Abstract
Co-repressor histone deacetylase 9 (HDAC9) plays a key role in the development and differentiation of many types of cells, including regulatory T cells. However, the biological function of HDAC9 in T effector cells is unknown. Systemic autoimmune diseases like lupus, diabetes, and rheumatoid arthritis have dysfunctional effector T cells. To determine the role of HDAC9 in systemic autoimmunity, we created MRL/lpr mice with HDAC9 deficiency that have aberrant effector T cell function. HDAC9 deficiency led to decreased lympho-proliferation, inflammation, autoantibody production, and increased survival in MRL/lpr mice. HDAC9-deficient mice manifested Th2 polarization, decreased T effector follicular cells positive for inducible co-stimulator, and activated T cells in vivo compared with HDAC9-intact MRL/lpr mice. HDAC9 deficiency also resulted in increased GATA3 and roquin and decreased BCL6 gene expression. HDAC9 deficiency was associated with increased site-specific lysine histone acetylation at H3 (H3K9, H3K14, and H3K18) globally that was localized to IL-4, roquin, and peroxisome proliferator-activated receptor-γ promoters with increased gene expression, respectively. In kidney and spleen, HDAC9 deficiency decreased inflammation and cytokine and chemokine production due to peroxisome proliferator-activated receptor γ overexpression. These findings suggest that HDAC9 acts as an epigenetic switch in effector T cell-mediated systemic autoimmunity.
Highlights
Ger naïve CD4ϩ T cells to differentiate into skewed effector or regulatory T cell populations, upsetting normal homeostasis
histone deacetylase 9 (HDAC9) Is Overexpressed in Different Subsets of CD4ϩ T Cells in MRL/lpr Mice and Human Lupus CD4ϩ T Cells—To determine which histone deacetylases (HDACs) play a role in systemic CD4 T cell-mediated autoimmunity, we performed real-time quantitative PCR in splenocytes from MRL/lpr mice and control MRL/MpJ mice
There was no significant difference in expression of HDAC4, -5, or -7 mRNA between the two groups of mice
Summary
T-reg, regulatory T cell; Tfh, T follicular helper; Th, T helper: HDAC, histone deacetylase; ICOS, inducible co-stimulator; WT, MRL/lprHDAC9ϩ/ϩ; KO, MRL/lprHDAC9Ϫ/Ϫ; DNT double negative T cells; miR-101, microRNA 101; PE, phosphatidylethanolamine; PPAR, peroxisome proliferator-activated receptor; NP, 4-hydroxy-3 nitrophenyl acetyl. We have observed site-specific hypoacetylation in different lysine residues of histone H3 and H4 that can be corrected by HDAC inhibitors in MRL/lpr mice in vivo [20] These results suggest that HDACs play a key role in the pathogenesis of systemic autoimmunity, lupus. Effector CD4ϩ T cells from MRL/lpr mice cannot be fully suppressed by T-reg cells due to diminished expression of CTLA4, CD80, and CD86 [21] These mice are valuable for elucidating the role of HDAC9 function in T effector cell-mediated autoimmunity independent of T-reg function. We demonstrate that HDAC9 deficiency leads to decreased systemic autoimmunity with increased survival and decreased immunoproliferation, decreased activated T cells, decreased ICOS-positive T effector cells and double negative T cells (DNT), increased Th2 polarization, autoantibody production, and kidney disease in MRL/lpr mice. Our findings in this study further elucidate the role of HDAC9 in CD4ϩ T cell effector-mediated systemic autoimmunity and may be useful in the future development of HDAC9 isoform-specific inhibitors for these conditions
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
