The role of effector regulatory T cells in immunity and pathology
Project type
PhD
| Supervisor(s) | Division | |
| (Primary) | Molecular Immunology | .(JavaScript must be enabled to view this email address) |
| (Co-supervisor) | Molecular Immunology | .(JavaScript must be enabled to view this email address) |
Details of project
Regulatory T cells (Tregs) are essential for the prevention of autoimmunity and death. We have identified a new population of effector or ‘active’ Tregs, and some of the proteins that are required for these cells to function. We now aim to examine the development of these cells in detail to illuminate their precise function, distribution and mode of action. This has potentially huge implications in treatment and diagnosis of autoimmunity, cancer or transplantation.
Foxp3+ regulatory T cells (Tregs) are essential for immune homeostasis and for the prevention of autoimmunity and death. Recent evidence indicates that Tregs can undergo specialised differentiation programs in the periphery. We demonstrate that expression of the transcriptional repressor Blimp1 defines a population of effector Tregs. We show that Blimp1 itself and another transcription factor, IRF4, are essential for most aspects of effector Treg differentiation, including IL-10 production and tissue homeostasis. We provide genetic evidence for the distinct nature of this population and some functional data; however, many details are currently unclear. In this study we will unravel the molecular requirements for the differentiation of effector Tregs and examine their precise function, distribution and mode of action.
We will address the following aims in this project:
- To elucidate the developmental pathway of effector Tregs - in the experiments proposed in this this aim we will characterise the effector Treg differentiation pathway and elucidate the function of IRF4 during effector Treg differentiation using a number of different molecular techniques.
- To characterise the migration pattern and tissue distribution of effector Tregs - our data show that effector Tregs display a distinct pattern of chemokine receptors some of which are directly regulated by Blimp1 and IRF4. We will examine the distribution of effector Tregs in lymphoid and non-lymphoid tissues in detail using immune-histochemistry and intravital microscopy.
- To uncover the essential role of effector Tregs - our data show that IRF4 and Blimp1 dependent effector Treg cells are a distinct subset of Tregs and we propose that these cells are the principal effector population of the Treg lineage, responsible for most if not all functions of Foxp3+ Tregs. We wish to directly test this hypothesis in new mouse models.
Project references
- Cretney E, Xin A, Shi W, Minnich M, Masson F, Miasari M, Belz G, Smyth GK, Busslinger M, Nutt SL, Kallies A. The transcription factors Blimp1 and IRF4 jointly control differentiation and function of effector regulatory T cells. Nat. Immunol. 2011 12:304-11.
- Lu, L. F. & Rudensky, A. Molecular orchestration of differentiation and function of regulatory T cells. Genes Dev. 2009 23:1270-1282.
- Campbell, D. J. & Koch, M. A. Phenotypical and functional specialization of FOXP3(+) regulatory T cells. Nat Rev Immunol. 2011 11:119-130.
Research interests
Our lab is interested in understanding the molecular events that regulate late-stage lymphocyte differentiation. This process is central to the immune system as it generates the effector populations that determine the ability of our body to control pathogens such as HIV or Plasmodium (the parasite that causes malaria) and to generate protective immunity after vaccination. However, the process of lymphocyte differentiation is also intimately linked to autoimmune disease and leukaemia. Thus, a thorough understanding of the key molecules involved in the peripheral differentiation of B and T cells (the main lymphocytic lineages) is central to any therapeutic approach for treating immunodeficiencies, blood cell-derived cancers or autoimmunity.
Our lab utilises a number of transgenic and knock-out mouse models such as green fluorescent protein (GFP)-based transcription factor reporter mice as well as infection models such as influenza and lymphocytic choriomeningitis virus (LCMV). We are utilising a broad range of molecular techniques including next-generation sequencing, microarrays, real-time PCR and chromatin immunoprecipitation (ChIP).
Selected publications
- Kallies A, Hawkins ED, Belz GT, Metcalf D, Hommel M, Corcoran LM, Hodgkin PD and Nutt SL. Transcriptional repressor Blimp-1 is essential for T cell homeostasis and self tolerance. Nat. Immunol. 20067:466-74.
- Kallies A, Hasbold J, Fairfax K, Pridans C, Emslie D, McKenzie BS, Lew AM, Corcoran LM, Hodgkin PD, Tarlinton DM and Nutt SL. Initiation of plasma cell differentiation is independent of Blimp-1. Immunity 2007 26:555-66.
- Nutt SL, Fairfax K and Kallies A. Blimp-1 guides the fate of effector B and T cells. Nat. Rev. Immunol. 2007 7:923-7.
- Kallies A. Distinct regulation of effector and memory T cell differentiation. Immunol. Cell. Biol. 2008 86:325-32.
- Kallies A, Xin A, Belz GT, Nutt SL. Blimp1 Is Required For the differentiation of protective effector CD8+ T cells and memory responses. Immunity. 2009 31:283-95.
- Kallies A, Carotta S, Huntington ND, Bernard NJ, Tarlinton DM, Smyth MJ, Nutt SL. A role for Blimp-1 in the transcriptional network controlling natural killer cell maturation. Blood. 2010 117:1869-79.
Research theme
Infectious diseases
Scientific discipline
- Autoimmunity
- Cell Biology
- Immunology
- Molecular Biology
Keywords
lymphocytes, transcription factors, regulatory T cells, molecular