Histone Deacetylation Inhibitors as Modulators of Regulatory T Cells

Abstract

Regulatory T cells (Tregs) are important mediators of immunological self-tolerance and homeostasis. Being cluster of differentiation 4+Forkhead box protein3+ (CD4+FOXP3+), these cells are a subset of CD4+ T lymphocytes and can originate from the thymus (tTregs) or from the periphery (pTregs). The malfunction of CD4+ Tregs is associated with autoimmune responses such as rheumatoid arthritis (RA), multiple sclerosis (MS), type 1 diabetes (T1D), inflammatory bowel diseases (IBD), psoriasis, systemic lupus erythematosus (SLE), and transplant rejection. Recent evidence supports an opposed role in sepsis. Therefore, maintaining functional Tregs is considered as a therapy regimen to prevent autoimmunity and allograft rejection, whereas blocking Treg differentiation might be favorable in sepsis patients. It has been shown that Tregs can be generated from conventional naïve T cells, called iTregs, due to their induced differentiation. Moreover, Tregs can be effectively expanded in vitro based on blood-derived tTregs. Taking into consideration that the suppressive role of Tregs has been mainly attributed to the expression and function of the transcription factor Foxp3, modulating its expression and binding to the promoter regions of target genes by altering the chromatin histone acetylation state may turn out beneficial. Hence, we discuss the role of histone deacetylation inhibitors as epigenetic modulators of Tregs in this review in detail.

The Chromatin Accessibility Landscape of Peripheral Blood Mononuclear Cells in Patients With Systemic Lupus Erythematosus at Single-Cell Resolution

“…T-1 showed a decreased cell number ratio and abnormal signals related to histone binding and the histone acetyltransferase complex. This result indicates that T-1 may consist of CD4+ T cells and therefore experience a differentiating response to inflammation, as histone acetylation contributes to the expression of genes involved in regulatory T cell differentiation and function, including increased Foxp3 stability ( 33 ).…”

Dysregulated epigenetic modifications in psoriasis

“…HDAC-1 has been shown to be upregulated in psoriatic skin. 72,73 Previous studies have shown that HDAC inhibition regulates Treg function 74 by increasing Foxp3 expression 75 and preventing production of IL-17A. 76 As Treg plays an important role in the pathogenesis of psoriasis, 77 HDAC may be important for immune regulation in psoriasis.…”

Epigenetic Modifiers: Anti-Neoplastic Drugs With Immunomodulating Potential

“…Its expression is regulated epigenetically ( 125 ). Foxp3 associates with HAT (p300 or TIP60) ( 126 ) as well as HDAC (SIRT1 or HDAC5) ( 127 ) pointing HAT inhibitors (HATi) as potential drugs for inhibiting Treg function ( 128 ). In Treg, replacement of a repressor complex at the Foxp3 promoter by the HAT p300/CREB-binding protein-associated factor (PCAF) is key to enable permissive histone modifications and as such making the Foxp3 promoter accessible ( 129 ).…”