Histone/protein deacetylases and T-cell immune responses

Abstract

Clinical and experimental studies show that inhibition of histone/protein deacetylases (HDAC) can have important anti-neoplastic effects through cytotoxic and proapoptotic mechanisms. There are also increasing data from nononcologic settings that HDAC inhibitors (HDACi) can exhibit useful anti-inflammatory effects in vitro and in vivo, unrelated to cytotoxicity or apoptosis. These effects can be cell-, tissue-, or context-dependent and can involve modulation of specific inflammatory signaling pathways as well as epigenetic mechanisms. We review recent advances in the understanding of how HDACi alter immune and inflammatory processes, with a particular focus on the effects of HDACi on T-cell biology, including the activation and functions of conventional T cells and the unique T-cell subset, composed of Foxp3(+) T-regulatory cells. Although studies are still needed to tease out details of the various biologic roles of individual HDAC isoforms and their corresponding selective inhibitors, the anti-inflammatory effects of HDACi are already promising and may lead to new therapeutic avenues in transplantation and autoimmune diseases.

Figure 1

Effects of HDACi on the interactions of Tregs, APCs, and effector T cells. Epigenetic events are displayed according to each stage of T-cell maturation (boxes) and matched with corresponding HDACi effects as shown in the outer row of arrows. (Middle) Treg, APC, and T-cell interactions, cytokine production, reciprocal stimulatory and inhibitory signals, and effects of HDACi on Tregs and pro-inflammatory APC (top boxes); the suppressive effects of Tregs are not shown.

Figure 2

HDACi promote the rapid down-regulation of CD62L, a marker of naive T cells. Freshly isolated murine CD4⁺ and CD8⁺ T cells, and Tregs, exposed to low, nontoxic concentrations of a pan-HDACi showed CD62L down-regulation within 2 hours of exposure, illustrating the potential for phenotypic modulation of T cells independently of their cell division.

Figure 3

Effects of inflammatory and/or immune stimuli on T-cell activation and their modulation by HDACi. (Left panel) How multiple mechanisms promote Teff cell resistance to Treg suppression, impair Treg function, and inhibit the development of iTregs. Intervention points for HDACi, as identified from the current literature, are indicated in red balls (inhibition) and green balls (stimulation). (Right panel) Mechanisms by which HDACi can promote resolution of inflammation, including through modulation of T-cell activation and enhancement of Treg suppressive functions.