Our in vivo studies in mice indicate that histone deacetylase inhibitors (HDACi) enhance the numbersand/or suppressive function of regulatory T cells (Tregs), through effects on Foxp3+ cell production, andhistone and FoxpS acetylation. We propose to explore aspects of HDACi use with relevance to experimentalmodels 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 functionalactivity, and that HDACi therapy can enhance Treg functions in vitro and in vivo. Our proposed studies willdetermine if HDACi therapy: 1.1) increases Treg numbers by affecting thymic production, peripheralconversion or increased lifespan; 1.2) increases Treg suppressive functions; 1.3) has effects on non-Tregs thatmay explain the therapeutic effects observed in vivo; 1.4) depends on the use of a particular agent or is ageneral action of HDACi on Tregs; 1.5) is enhanced by combination with immunosuppression; and 1.6) isenhanced by combination with DNA methyltransferase inhibitors?Aim #2: Which HDACs are involved and what are they affecting in Tregs? Based on our initial data ofHDACi 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 investigatethe following: 2.1) does the prototypic class II HDAC, HDAC9, control Treg numbers, gene expression andfunction; 2.2) how is HDAC9 regulated, and is the catalytic activity of HDAC9 required for its effects inTregs; 2.3) do class I HDACs also contribute to the regulation of Treg function; and 2.4) is acetylation ofFoxp3 itself a key regulator of Treg functions?This project will complement projects #1 and #2 by testing in vivo key concepts and insights developedby the detailed biochemical studies of the FoxpS complex in project #1, and the various structure/functionrelationships for FoxpS arising from project #2. Project 3 will also rely on access to appropriate transgenicand mutant mice developed by the Transgenic Core.We anticipate that our studies will have two main benefits for the broad scientific community andultimately for clinical care. First, they will likely provide the basic insights into how immune monitoring canmove beyond the current state of was FoxpS detected or not? i.e. important new criteria for evaluation of thelevel 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 Tregfunctions in vivo, and will likely also suggest important new targets for future therapeutic targeting (e.g.HDAC9-selective blockade).
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