Class IIA HDACs are a widely expressed, conserved family of transcriptional regulators with crucial roles in development and disease. Their activity is controlled via phosphorylation of N-terminal serine residues that dictate nuclear vs. cytoplasmic localization, which in turn determines what target transcription factors (e.g., MEF2) are bound by an N-terminal adapter domain. At most sites, class IIA HDACs repress target loci either by direct binding – converting activators into repressors – or as part of a large NCoR/SMRT-HDAC3 corepressor complex.
HDAC7 is a class IIA member highly expressed in developing thymocytes, and we have uncovered crucial roles for this protein in controlling multiple aspects of T-cell development. In conventional T-cells, loss of HDAC7 strongly inhibits positive selection by shortening thymocyte lifespan and altering tonic MAPK activity. In contrast, a gain of function HDAC7 mutant (HDAC7-ΔP, where N-terminal serines are mutated to prevent nuclear export) results in a robust block in negative selection and the escape of autoreactive T-cells out into the periphery.
Building on this previous work in conventional (naïve) T-cells, the Verdin lab is now focused on understanding the role of HDAC7 in the development of so-called agonist-selected T-cells. This class of T-cells, including tTregs, invariant natural killer T-cells (iNKTs), CD8 intraepitheilial cells (IELs), and MR1-associated invariant T-cells (MAIT), are thought to receive stronger than-normal TCR signals during thymic residence yet manage to escape negative selection and leave the thymus as non-naïve effectors. We believe we have uncovered a crucial role for HDAC7 in regulating the development of these agonist-selected T-cells by licensing the acquisition of the innate effector pathway that gives them many mature effector properties (non-circulating tissue residence, robust cytokine production ability and limited proliferative potential).
Interestingly, the gain-of-function HDAC7-ΔP mutant develops striking tissue-specific autoimmunity characterized by obliterative exocrine pancreatitis and extensive lymphocytic infiltrates in stomach, liver, and intestine. We hypothesize that the combination of blocked negative selection in conventional T-cells and disruption in the development of homeostatic innate effectors contributes to this constellation of tissue-specific autoimmunity. HDAC7 has been implicated in GWAS studies as containing susceptibility loci for both primary sclerosing cholangitis (PSC) and inflammatory bowel disease, and we believe that our work holds important therapeutic implications in ameliorating and treating these autoimmune conditions.
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2. Kasler HG, Young BD, Mottet D, Lim HW, Collins AM, Olson EN, Verdin E. Histone deacetylase 7 regulates cell survival and TCR signaling in CD4/CD8 double-positive thymocytes. J Immunol. 186(8): 4782-93 (2011) PMID: 21398603
3. Parra M, Mahmoudi T, Verdin E. Myosin phosphatase dephosphorylates HDAC7, controls its nucleocytoplasmic shuttling, and inhibits apoptosis in thymocytes. Genes Dev. 21(6); 638-43 (2007) PMID: 17369396
4. Dequiedt F, Kasler H, Fischle W, Kiermer V, Weinstein M, Herndier BG, Verdin E. HDAC7, a thymus-specific class II histone deacetylase, regulates Nur77 transcription and TCR-mediated apoptosis. Immunity. 18(5) 687-98 (2003) PMID: 127574
Maintaining the ability to mount adaptive immune responses against potential pathogens is crucial for survival, but is costly in terms of the potential for autoimmunity. Autoimmune disease is a leading cause of morbidity and mortality in the developed world, and the ongoing identification of autoimmune mechanisms behind previously poorly understood pathologies suggests that the true burden is underestimated. CD4+ T cells are key players in mounting adaptive immune responses to invading pathogens. Upon their initial activation from a naïve state, CD4+ T cells differentiate into various effector and regulatory lineages with unique functions. IL17A-secreting Th17 cells are one of CD4+ T cell subsets that protect the body from pathogens, especially extracellular bacteria in the gastrointestinal tract by recruiting neutrophils and macrophages to the site of infection. However, hyper-activation of Th17 cells against autoantigen can cause or exacerbate various autoimmune conditions. In contrast, regulatory T (Treg) cells are active arm of weapons that endeavor to maintain immune homeostasis, typically by negatively regulating a diverse array of immune responses in diverse contexts ranging from cancer to inflammation.
The sirtuins are a class of NAD+-dependent enzymes that remove acyl-CoA-derived posttranslational modifications from a large number of proteins, thereby regulating their functions and have been broadly implicated in metabolism and aging. In mammals, SIRT1 in particular acts as a critical regulator that modulates the activity of several transcription factors important for immune function. While initial studies on globally Sirt1-deficient mice suggested that SIRT1 has a primarily anti-inflammatory function, more recent work focusing on T cells has identified an important pro-inflammatory action.
Increasing evidence suggests that Treg and Th17 cells are not stable cell lineages. In certain microenvironments, Treg and Th17 cells exhibit considerable “plasticity” and can change their function and phenotype. Imbalanced systemic or local Treg/Th17 cells ratios are associated with various malignancies, autoimmune disorders, and immune aging. Recently, we have discovered that SIRT1 functions as a crucial molecular switch in controlling Treg and Th17 cell differentiation. Based on these findings, we are continuing to investigate molecular and cellular mechanisms regulating Treg/Th17 cells development and plasticity with the ultimate goal of developing methodologies to modulate Treg/Th17 cells balance for in vivo therapeutic intervention.
1. Hyung W. Lim, Seung Goo Kang, Jae Kyu Ryu, Birgit Schilling, Mingjian Fei, Intelly S. Lee, Amanuel Kehasse, Kotaro Shirakawa, Masaru Yokoyama, Martina Schnölzer, Herbert G. Kasler, Hye-Sook Kwon, Bradford W. Gibson, Hironori Sato, Katerina Akassoglou, Changchun Xiao, Dan R. Littman, Melanie Ott, and Eric Verdin "SIRT1 deacetylates RORγt and enhances Th17 cell generation" Journal of Experimental Medicine, 2015, 212 (5), 607-617 (highlighted in Nature Reviews Drug Discovery, ScienceDaily News, Multiple Sclerosis News Today, San Francisco Business Times, and Gladstone News)
2. Hye-Sook Kwon*, Hyung W. Lim*, Jessica Wu, Martina Schnoelzer, Eric Verdin, and Melanie Ott "Three novel acetylation sites in the Foxp3 transcription factor regulates the suppressive activity of regulatory T cells." (*Co-first author), Journal of Immunology, 2012, 188: 2712-2721