Gray-Projects

Gray-Projects

Projects

Epithelial cell behaviour in thymus maintenance and regeneration

T cells are made in the thymus. Their differentiation and tolerance of the body’s tissues is directed by signals from epithelial cells. We aim to elucidate the signalling networks and apoptotic processes that form and maintain the epithelium of the thymus. Leveraging this knowledge to understand how defects in these pathways contribute to autoimmune disease and immunodeficiency is a key focus of this program, with a view to correcting these problems via cell therapies or targeted small molecules.

Project resources

  • Sheridan JM, Keown A, Policheni A, Roesley SNA, Rivlin N, Kadouri N, Ritchie ME, Jain R, Abramson J, Heng TSP, Gray DHD. Thymospheres are formed by mesenchymal cells with the potential to generate adipocytes but not epithelial cells. Cell Rep. 2017. 21; 934-942. PMID: 29069601
  • Jain R, Sheridan JM, Policheni AN, Heinlein M, Gandolfo LC, Dewson G, Smyth GK, Sansom SN, Fu, NY, Visvader JE, Hollander GA, Strasser A, Gray DHD. A critical epithelial survival axis regulated by MCL-1 maintains thymic epithelial cell function in mice. Blood. 2017. 130 (23): 2504-2515. PMID: 28972012

Team members: Dr Julie Sheridan, Ms Melanie Heinlein

 

Microscopic image of the thymus
'Thymus Wreath' by Melanie Heinlein, 2016

 

FOXP3+ Regulatory T cell death and homeostasis in health and disease

FOXP3+ Regulatory T (Treg) cells dampen immune responses and are critical for the maintenance of immune tolerance.

In this project we seek to understand the molecular control of Treg cell survival, with a view to finding unique properties that could be therapeutically targeted to modulate their potent immune function in disease. 

Project resources

  • Teh CE, Lalaoui N, Jain R, Policheni AN, Heinlein M, Alvarez-Diaz S, Sheridan JM, Rieser E, Deuser S, Darding M, Koay HF, Hu Y, Kupresanin F, O'Reilly LA, Godfrey DI, Smyth GK, Bouillet P, Strasser A, Walczak H, Silke J, Gray DH. Linear Ubiquitin Chain Assembly Complex  Coordinates Late Thymic T Cell Differentiation and Regulatory T Cell Homeostasis Nat. Comm. 2016 Nov 18;7:13353. doi: 10.1038/ncomms13353 PMID: 27857075 
  • Pierson, Cauwe, Policheni, Schlenner, Franckaert, Berges, Humblet-Baron, Schonefeldt, Herold, Hildeman, Strasser, Bouillet, Lu, Matthys, Freitas, Luther, Weaver, Dooley, Gray DH*, Liston A* . Antiapoptotic Mcl-1 is critical for the survival and niche-filling capacity of Foxp3+ regulatory T cells. Nat. Immunol. 2013 Sep;14(9):959-65. PMID: 23852275
  • Liston A, Gray DH. Homeostatic control of regulatory T cell diversity. Nat. Rev. Immunol. 2014 Mar 14(3):154-65 PMID: 24481337

* joint last authors

Team member: Dr Charis Teh, Dr Antonia Policheni, Ms Alissa Robbins

 

 

Mass cytometric analysis of cell death during cancer treatment

Cell death is directly controlled by more than 80 different proteins. We are using a new technology called mass cytometry (or CyTOF) to resolve the critical changes that occur in cells engaged in making the decision to live or die. This approach allows us to measure more than 40 critical parameters in millions of individual cells. We analyse these data with machine learning and bioinformatic approaches to determine how to kill cancer cells more effectively to treat cancer.

Team members: Dr Charis Teh, Dr Clare Weeden, Ms Tania Tan