The immune response requires a delicate balance between activation and attenuation. Likewise, therapies for autoimmune diseases and organ transplantation face the challenge of achieving enough immunosuppression to prevent organ rejection or limit autoreactivity without impairing the host's ability to protect against infections and malignancy. Regulatory T-cells (Treg) are an important T-cell subset crucial to self-tolerance, capable dampening or switching off antigen-specific immune responses (1). The transcription factor Forkheadbox-p3 (Foxp3) plays a key role in the development and functions of Treg. Foxp3 is regulated transcriptionally but also by post-translational modifications. We have shown that acetylation of lysine residues within the Foxp3 protein can enhance Treg function (2). Such acetylation also protects Foxp3 from proteasomal degradation and thus contributes to optimal Treg functions. Foxp3 acetylation is regulated by the competing actions of several histone/protein acetyltransferases (HAT) and histone/protein deacetylases (HDAC). We propose to study the role of Sirtuin-1 (Sirt1), a class III HDAC highly conserved across eukaryotic species and an important mediator of cellular metabolism and longevity, in Tregs. We have begun to exploit use of mice with targeted deletions of Sirt1, which is important as mice with global Sirt1 knockout suffer from metabolic problems and shortened lifespan. In addition, we have employed Sirt1 small molecule inhibitors to test the effect of transient Sirt1 inhibition in wild-type mice. Our preliminary data show that the targeted deletion of Sirt1 increases the acetylation and expression of Foxp3, and enhances the immunosuppressive functions of Treg. In addition, deletion of Sirt1 in Tregs, or its pharmacologic inhibition, attenuates allograft rejection and prolongs survival of murine cardiac allografts. Therefore, our central hypothesis is that targeting Sirt1 may have therapeutic value in autoimmunity and transplantation.
Our aims are to explore how Sirt1 deletion or inhibition: 1) improves allograft survival and function (in murine recipients with induced diabetes and renal failure);2) alleviates autoimmunity (in murine inflammatory bowel disease models);and, further, understand 3) distinct molecular mechanisms how Sirt1 influences T-cell biology beyond simply promoting Foxp3 acetylation. Our findings will likely prove important to the development of new immunomodulatory strategies for application in autoimmunity and transplantation. Our proposed studies are also important for an increased understanding of the functions of Sirt1 in immune responses, given the rising attention being given to the Sirt1 activator resveratrol (already available over the counter) and other more potent small molecule Sirt1 activators (3), for therapy of various diseases and for promotion of overall well-being. In addition, Sirt1 inhibitors are under consideration as anti-neoplastic drugs (4). Therefore, we caution that it is critical to learn more about the role of Sirt1 in the immune system as such treatment options are evolving.

Public Health Relevance

(provided by applicant): We study Sirtuin-1 as a novel therapeutic target to attenuate the immune response, which is relevant to improve treatment options to achieve immunosuppression, e.g. for patients suffering from self-reactive immune disease, or recipients of an organ transplant. Furthermore, it is important to learn more about the role of Sirtuin-1 in the immune system, as many investigators pursue Sirtuin-1 enhancement (diabetes mellitus, metabolic syndrome), or Sirtuin-1 suppression (certain cancers).

Agency
National Institute of Health (NIH)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AI095353-04
Application #
8632987
Study Section
Transplantation Biology &Immunology-2 (AITC)
Program Officer
Prograis, Lawrence J
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Liu, Yujie; Wang, Liqing; Han, Rongxiang et al. (2014) Two histone/protein acetyltransferases, CBP and p300, are indispensable for Foxp3+ T-regulatory cell development and function. Mol Cell Biol 34:3993-4007
Akimova, T; Xiao, H; Liu, Y et al. (2014) Targeting sirtuin-1 alleviates experimental autoimmune colitis by induction of Foxp3+ T-regulatory cells. Mucosal Immunol 7:1209-20
Wang, Liqing; Liu, Yujie; Beier, Ulf H et al. (2013) Foxp3+ T-regulatory cells require DNA methyltransferase 1 expression to prevent development of lethal autoimmunity. Blood 121:3631-9
Wang, Liqing; Liu, Yujie; Han, Rongxiang et al. (2013) Mbd2 promotes foxp3 demethylation and T-regulatory-cell function. Mol Cell Biol 33:4106-15
Liu, Yujie; Wang, Liqing; Predina, Jarrod et al. (2013) Inhibition of p300 impairs Foxp3? T regulatory cell function and promotes antitumor immunity. Nat Med 19:1173-7
Liu, Yujie; Wang, Liqing; Han, Rongxiang et al. (2012) Two lysines in the forkhead domain of foxp3 are key to T regulatory cell function. PLoS One 7:e29035
Akimova, Tatiana; Beier, Ulf H; Liu, Yujie et al. (2012) Histone/protein deacetylases and T-cell immune responses. Blood 119:2443-51
Beier, Ulf H; Akimova, Tatiana; Liu, Yujie et al. (2011) Histone/protein deacetylases control Foxp3 expression and the heat shock response of T-regulatory cells. Curr Opin Immunol 23:670-8