Final Report Summary - TREG (Analysis of regulatory T cell proliferation and apoptosis in vivo at the cellular and molecular level) Progress towards objectives- Aim 1. To characterise the cellular properties of Foxp3+ regulatory T cells in regards to homeostasis, proliferation and apoptosis (Period 1)- Aim 2. To test the role of Bcl-2 family members in controlling the proliferative and apoptotic properties of Foxp3+ regulatory T cells (Period 2)- Aim 3. To test the role of the Pdl / IL-2 axis in modulating Foxp3+ regulatory T cell numbers during inflammation (Period 2)Description of work performed- Foxp3DTR/Thy1.1 system setup and optimised - Kinetics of regulatory T cell reconstitution measured- Contribution of proliferation and apoptosis to regulatory T cell reconstitution measured- Role of Bcl2, BclX, Mcl1 in regulatory T cell homeostasis assessed- Role of Bim, Bak/Bad in regulatory T cell homeostasis assessed- Role of dendritic cells, IL-2 and costimulation in regulatory T cell homeostasis assessed- Construct and mice for IL2 over-expression generatedDescription of main results- Identification of Mcl1 as the primary factor for regulatory T cell homeostasis- Determination that Bcl2 and BclX play little role in regulatory T cell homeostasis- Identification of Bak/Bax as key regulators of regulatory T cell number- Identification of Bim as key regulators of regulatory T cell number- Identification of costimulation, but not dendritic cells, as key regulators of regulatory T cell homeostasis- Identification of IL-2 effect on Mcl1 and survival- Analysis of kinetics of regulatory T cell response to disturbed homeostasisPotential impact- Aid in the future design of therapeutics to alter regulatory T cell number. Patent submitted for gene-therapy use- Eg identification of Mcl1 as key drug target. Patent submitted for gene-therapy use- Development would have large impact on patients with autoimmune disease
