MOLECULAR IMMUNOLOGY

• Staff
  • Laboratory Head
  • Scientific Staff
  • Research Staff
  • Students
• Goals
• Research Projects
  1. Molecular identification of Regulatory T cells
  2. Novel biomarkers on human Regulatory T cells
  3. FOXP3 as a novel tumour suppressor in breast cancer

STAFF

Laboratory Head

Associate Prof. Simon Barry

Ph: 08 8161 6562

Email: simon.barry@adelaide.edu.au

Scientific Staff

Research Staff

Students

GOALS

To improve our understanding of regulatory T cell function through studies of gene expression, transcription factors and surface molecules and to develop regulatory T cells for cell therapy.

RESEARCH PROJECTS

1. Molecular identification of Regulatory T cells

The recent identification of regulatory T cells (Tregs) as a key mediator of central and peripheral tolerance has led to an increase in our understanding of the cellular mechanisms. The identification of a transcription factor named FoxP3 in both mouse and human Tregs defines a committed T cell subset that has regulatory capacity. There is however, very little known about the molecular basis of this process. This project aims to identify the genes directly regulated by FoxP3 and to determine their role in the regulatory phenotype. We have used a number of direct and indirect molecular approaches such as Chromatin Immunoprecipitation and microarray analysis to profile genes regulated by FOXP3, and were the first to identify the FOXP3 targets in human Treg. We validate their role in regulatory function by direct assays and by over expression or gene ablation studies. We have focussed on the gene regulation networks in human Treg and discovered a number of transcription factors and microRNAs whose expression appears to be tightly controlled by FOXP3, and we are now actively investigating the regulation of these genes and their downstream targets. The candidate genes identified in this approach may lead to therapeutic approaches for intervention in the function of regulatory cells, and will also have application for diagnostic analysis of regulatory cell function

2. Novel biomarkers on human Regulatory T cells

The current best practice for identifying human regulatory T cells relies on intracellular detection of the expression of FOXP3, but this renders the cell functionless. There is hence a need for cell surface markers on human Treg that can be used to isolate functional Treg. Our genome wide discovery project demonstrated that the human Treg have a significant number of cell surface molecules up or down regulated. In partnership with the CRC for Biomarker translation, we are developing reagents against a number of these molecules, including the novel human Treg biomarker peptidase inhibitor (PI16). PI16 appears to be expressed on a subset of natural human regulatory T cells, and may provide a new tool for the analysis of Treg in health and disease.

3. FOXP3 as a novel tumour suppressor in breast cancer

Given the recent observations that a significant number of human breast cancer samples have mutations in FOXP3, and that the female FoxP3 null scurfy mice are prone to breast cancer, we sought to understand the molecular mechanisms that may underpin this association. As we have a comprehensive list of FOXP3 target genes in Treg, we postulated that FOXP3 may also be able to regulate some of these genes in breast epithelial cells. We then analysed our dataset for potential oncogenes and identified SATB1 as a candidate target. Using breast cancer cell lines we have demonstrated that FOXP3 does down regulate this oncogene, and that it also regulates the gene via micro RNASs. This provides evidence that FOXP3 can function outside of Treg, and may have a key role in tumour suppression.

Cell surface expression of PI16 on >60% of human FOXP3+ve CD4+ CD25+Treg

A model for the tumour suppressor action of human FOXP3