Our in vivo studies in mice indicate that histone deacetylase inhibitors (HDACi) enhance the numbers and/or suppressive function of regulatory T cells (Tregs), through effects on Foxp3+ cell production, and histone and FoxpS acetylation. We propose to explore aspects of HDACi use with relevance to experimental models of transplant rejection and autoimmunity.
Aim #1 : Does the balance between acetylation and deacetylation regulate Treg-dependent functions? Our preliminary studies indicate that Foxp3+ CD4+CD25+ Tregs have considerable HDAC functional activity, and that HDACi therapy can enhance Treg functions in vitro and in vivo. Our proposed studies will determine if HDACi therapy: 1.1) increases Treg numbers by affecting thymic production, peripheral conversion or increased lifespan;1.2) increases Treg suppressive functions;1.3) has effects on non-Tregs that may explain the therapeutic effects observed in vivo;1.4) depends on the use of a particular agent or is a general action of HDACi on Tregs;1.5) is enhanced by combination with immunosuppression;and 1.6) is enhanced by combination with DNA methyltransferase inhibitors? Aim #2: Which HDACs are involved and what are they affecting in Tregs? Based on our initial data of HDACi affecting the size and the function of the Foxp3+ Treg pool, and data from our analysis of HDAC9- deficient mice showing increased numbers and suppressive function of Foxp3+ Tregs, we will investigate the following: 2.1) does the prototypic class II HDAC, HDAC9, control Treg numbers, gene expression and function;2.2) how is HDAC9 regulated, and is the catalytic activity of HDAC9 required for its effects in Tregs;2.3) do class I HDACs also contribute to the regulation of Treg function;and 2.4) is acetylation of Foxp3 itself a key regulator of Treg functions? This project will complement projects #1 and #2 by testing in vivo key concepts and insights developed by the detailed biochemical studies of the FoxpS complex in project #1, and the various structure/function relationships for FoxpS arising from project #2. Project 3 will also rely on access to appropriate transgenic and mutant mice developed by the Transgenic Core. We anticipate that our studies will have two main benefits for the broad scientific community and ultimately for clinical care. First, they will likely provide the basic insights into how immune monitoring can move beyond the current state of was FoxpS detected or not? i.e. important new criteria for evaluation of the level of activation and functional competency of Foxp3+ Tregs should be generated by our work. Second, they are likely to provide the basis for the rational use of HDACi for pharmacologic enhancement of Treg functions in vivo, and will likely also suggest important new targets for future therapeutic targeting (e.g. HDAC9-selective blockade).

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI073489-05
Application #
8378836
Study Section
Special Emphasis Panel (ZAI1-SV-I)
Project Start
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$482,526
Indirect Cost
$85,733
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Akimova, Tatiana; Levine, Matthew H; Beier, Ulf H et al. (2016) Standardization, Evaluation, and Area-Under-Curve Analysis of Human and Murine Treg Suppressive Function. Methods Mol Biol 1371:43-78
Xiao, Haiyan; Jiao, Jing; Wang, Liqing et al. (2016) HDAC5 controls the functions of Foxp3(+) T-regulatory and CD8(+) T cells. Int J Cancer 138:2477-86
Levine, Matthew H; Wang, Zhonglin; Xiao, Haiyan et al. (2016) Targeting Sirtuin-1 prolongs murine renal allograft survival and function. Kidney Int 89:1016-26
Beier, Ulf H; Angelin, Alessia; Akimova, Tatiana et al. (2015) Essential role of mitochondrial energy metabolism in Foxp3⁺ T-regulatory cell function and allograft survival. FASEB J 29:2315-26
Chen, Yongheng; Chen, Chunxia; Zhang, Zhe et al. (2015) DNA binding by FOXP3 domain-swapped dimer suggests mechanisms of long-range chromosomal interactions. Nucleic Acids Res 43:1268-82
Deng, Guoping; Nagai, Yasuhiro; Xiao, Yan et al. (2015) Pim-2 Kinase Influences Regulatory T Cell Function and Stability by Mediating Foxp3 Protein N-terminal Phosphorylation. J Biol Chem 290:20211-20
Wang, Liqing; Liu, Yujie; Han, Rongxiang et al. (2015) FOXP3+ regulatory T cell development and function require histone/protein deacetylase 3. J Clin Invest 125:1111-23
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
Xiao, Yan; Nagai, Yasuhiro; Deng, Guoping et al. (2014) Dynamic interactions between TIP60 and p300 regulate FOXP3 function through a structural switch defined by a single lysine on TIP60. Cell Rep 7:1471-80

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