SIRT1 and Immunity
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