GENERATION OF INTRATHYMIC MICROENVIRONMENTS TO ESTABLISH T-CELL TOLERANCE

Lead Research Organisation: University of Birmingham
Department Name: Immunity and Infection

Abstract

White blood cells called T-cells are an essential component of the immune system, a body-wide series of cells and organs that is essential for life. T-cells are directly required to fight against bacterial and viral infections, as well as to help other immune system cells to make antibodies. The thymus is an immune organ in the chest that is the exclusive site for the production of T-cells. The importance of T-cells and the thymus for the continued health of the individual can be seen in examples where thymus function is abnormal, which can result in immunodeficiency or autoimmunity, where T-cells are either absent or reactive towards to the bodies own tissues. Unlike many other organs, thymus function is not constant throughout life: it diminishes rapidly as we get older, meaning that fewer T-cell are produced as we age.

We aim to understand how T-cells are produced in the thymus by investigating how a specialised component of this organ, the thymic epithelium, develops and functions. By understanding how the thymus epithelium guides the production of T-cells, we hope to be able to apply this knowledge to the rejuvenation of thymus function, which will improve treatments where it is necessary to restore T-cell production, such as following bone marrow transplantation in the treatment of cancer.

Technical Summary

The thymus plays an essential role in supporting the development of T-cells from progenitors arising in the haemopoietic tissues. In addition, because of its importance in shaping the T-cell antigen receptor repertoire for self/non-self discrimination, the thymus is key in both the recognition of invading pathogens and in the avoidance of damaging autoimmune responses. Key to all these processes is the interaction between developing thymocytes and stromal cells constituting the thymic microenvironment. Studies from our laboratory have contributed to the growing understanding that epithelial cells in cortical and medullary micronvironments are key players, and that the functional dichotomy of thymic epithelial cells is reflected in their ability to regulate both positive and negative selection. While the requirements for thymocyte development provided by these stromal cells are becomingly increasingly understood, much less is known of the mechanisms regulating the development and specification of thymic epithelial cells themselves. The central aim of the current proposal is to define these mechanisms by characterizing thymic epithelial progenitors and the molecular processes that control their renewal and lineage specialization. The work will build on two key advances made in our current programme showing that cortical and medullary epithelial cells are derived from a common progenitor (Nature 2006) and that signaling involving TNF-Receptor family of molecules is essential in development of the thymic medulla and self-tolerance (J. Exp. Med. 2007). Specifically, we will analyse the development and persistence of bipotent thymic epithelial progenitors, including investigation of their persistence and regulation of lineage commitment. Together with studies aimed at optimizing a model of thymus transplantation currently in use for the treatment of Di George syndrome, such studies will aid future cell based strategies of thymus regeneration. In addition, by examining the mechanisms regulating formation of the thymic medulla for the regulation of self-tolerance, we will aid in understanding the mechanisms of central tolerance and the avoidance of autoimmunity.

Publications

10 25 50
 
Description Wellcome Trust Phd studentship
Amount £189,512 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2012 
End 09/2016
 
Description MRC Centre for Immune Regulation 
Organisation University of Birmingham
Department MRC Centre for Immune Regulation
Country United Kingdom 
Sector Academic/University 
PI Contribution Theme Lead Mechanisms in lymphocyte development and selection
Collaborator Contribution Core research facilities and Studentships
Impact All the outputs listed in this form
 
Description Regulation of intrathymic T-cell development 
Organisation University of Tokushima
Country Japan 
Sector Academic/University 
PI Contribution We have provided expertise in systems to manipulate thymic epithelial cells in vivo and in vitro
Collaborator Contribution Training in molecular biology/viral gene delivery
Impact White-AJ; Nakamura-K; Jenkinson-WE; Saini-M; Sinclair-C; Seddon-B; Narendran-P; Pfeffer-K; Nitta-T; Takahama-Y; Caamano-JH; Lane-P; Jenkinson-E; Anderson-G (2010). Lymphotoxin signals from positively selected thymocytes regulate the terminal differentiation of medullary thymic epithelial cells. J. Immnol. 185:4769-4776.
Start Year 2008
 
Description Role of RANK in Thymus development 
Organisation Austrian Academy of Sciences
Department Institute of Molecular Biotechnology
Country Austria 
Sector Academic/University 
PI Contribution Use of RANK KO mice to analyse importance of TNF receptors in medulla formation for t-cell tolerance
Collaborator Contribution Provision of RANK KO mice, experimental collaboration on the role of RANK in T-cell tolerance
Impact Rossi-SW, Kim-MY, Leibbrandt-A, Parnell-SM, Jenkinsom-WE, Glanville-SH, McConnell-FM, Penninger-J, Jenkinson-EJ, Lane-PJL and Anderson-G. (2007). RANK Signals From CD4+3- Inducer Cells Regulate Development of Aire-Expressing Epithelial Cells In The Thymic Medulla. J. Exp. Med 204:1267-1272.
Start Year 2006
 
Description Role of Retinoic Acid In Thymus Development 
Organisation Lund University
Department Faculty of Medicine
Country Sweden 
Sector Academic/University 
PI Contribution Generation of in vitro experimental systems to determine the role of Retinoic Acid on the development of thymic epithelial cells.
Collaborator Contribution Reciprocal scientific visits for postdocs and PhD students between Birmingham and Lund, to exchange key methodologies and reagents.
Impact Mesenchymal cells regulate retinoic acid receptor-dependent cortical thymic epithelial cell homeostasis. Sitnik KM, Kotarsky K, White AJ, Jenkinson WE, Anderson G, Agace WW. J Immunol. 2012 May 15;188(10):4801-9
Start Year 2010
 
Description THinkTank/University of Birmingham STEM 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Demonstrating laboratory techniques (eg DNA extraction to 500 adults and children)


School Mentoring activity with careers teachers - enhancing the view that Secondary school pupils have a of the career opportunities available to them
Year(s) Of Engagement Activity 2011,2012