Cell death control of regulatory T cell homeostasis

FOXP3+ regulatory T (Treg) cells are essential for restraining immune function. Their antagonism of autoimmune responses is crucial for health, but they also block responses to chronic infection and cancer. We are interested in how cell death processes shape the homeostasis of Treg cells with a view to modifying them to tailor immune responses. We have discovered the molecular control of Treg cell apoptosis under steady-state conditions (papers #2, 6, 7, 8) and recently defined a new pathway controlling the population during inflammation. This project will explore how to engage Treg cell death to improve responses to cancer and infection.

Team members: Dr Charis Teh, Dr Lucille Rankin, Dr Alissa Robbins

Single-cell resolution of cell death processes in blood cancer

In this project, we aim to direct new therapies for treating chronic lymphocytic leukaemia (CLL) and other blood cancers by using CyTOF and high parameter flow cytometry to resolve cell death pathways in millions of individual cancer cells from patients. By understanding how cancerous cells are impacted by new targeted therapies and adapt to resist them, we will be able to inform more effective treatments for CLL and other blood cancers (papers #3, 4).

Cell death and cancer
Figure 1. Single-cell resolution of cell death in myeloma. tSNE visualization of CyTOF analysis of myeloma cells undergoing apoptosis. Each dot represents a single cell arranged in space according to their similarity in 35-dimensions related to cell death proteins. Coloured according to time (left) or expression of apoptotic markers (right).

Team Members: Dr Charis Teh, Ms Tania Tan, Ms Mengxiao Luo

Thymic regeneration

The thymus is the exclusive site for differentiation of haematopoietic progenitors into the various T cell lineages. Curiously, although the thymus is essential for adaptive immunity, it is easily damaged and undergoes age-related atrophy to become virtually non-functional in adults. However, the thymus can be induced to regenerate and restore T cell immunity. This project focuses on the unique epithelial cells of the thymus that govern these processes. We use cutting edge imaging approaches to resolve how the thymic epithelium changes during involution and thymic regeneration to better understand how immune function might be restored (papers #1 and #5).

Figure 2. Imaging the thymus. Confocal image of a thymus section showing cortical (purple) and medullary (cyan) epithelium and apoptotic thymocytes (yellow). Made by Dr Julie Sheridan.

Team members: Ms Kelin Zhao

Epigenetic mechanisms controlling thymic tolerance

The autoimmune regulator, AIRE, induces the transcription of thousands of peripheral tissues genes in thymic epithelial cells to mediate immunological tolerance. Precisely how this remarkable process works at the molecular level is only beginning to be understood. We and others have found that the epigenetic state of the thymic epithelium is a critical determinant of AIRE function. Using novel genetic models, imaging approaches and flow cytometry, we aim to discover novel modifiers of this epigenetic state to understand how AIRE works to engender thymic tolerance.

H3K14ac AIRE
Confocal image of thymus sections showing AIRE (green) and H3K14 acetylation (red) in thymic cells. Made by Dr Melanie Heinlein.