Transcriptional regulation of innate immune cells protecting the intestinal tract
Project type
PhD
| Supervisor(s) | Division | |
| (Primary) | Molecular Immunology | .(JavaScript must be enabled to view this email address) |
Dr Erika Cretney (Co-supervisor) |
Molecular Immunology | .(JavaScript must be enabled to view this email address) |
Details of project
The intestine is the largest surface area in the body and forms a protective barrier shielding us from the external environment. It represents the first line of defence against invading pathogens and harbors ~10–100 trillion organisms. Immune regulatory networks in the intestine are critical to protect this tissue. Any breakdown leads to profound and progressive inflammatory disease of the gut.
Normally responses against daily insults from microorganisms and food antigens are well controlled, but in some cases, breakdown of the immune regulatory pathways results in destruction of intestinal villi, crypt hyperplasia and accumulation of leukocyte populations in the lamina propria and epithelium − in addition to the formation of new lymphoid aggregates along the intestine. This results in loss of oral tolerance, poor nutrient absorption, progressive inflammatory bowel disease and celiac disease. To maintain intestinal homeostasis, the immune system must balance symbiotic relationships between the host, dietary antigens and commensal bacteria.
Two major components of the gut protective apparatus - the gut-associated lymphoid tissues and CD4+ Treg cells - work in synergy to regulate intestinal lymphoid tissues in response to inflammation or pathogen invasion. A major question in the field is how the immune mechanisms that prevent intestinal breakdown are regulated. Innate immune cells such as lymphoid tissue inducer (LTi) cells, NKp46+ innate and Treg cells lay the foundation for lymphoid tissue formation (and hence the fundamental ability to mount an intestinal immune response) but precisely how they function to maintain immune homeostasis in health and disease is poorly defined.
Project Aims:
- Determine the transcriptional regulation of (a) LTi cells and (b) NKp46+ innate cells.
- Determine the lifecycle of LTi and NKp46+ cells at steady-state and during disease.
- Understand the transcriptional regulation of intestinal Treg cells at steady-state and during disease.
Project references
- Cretney E, Xin A, Shi W, Minnich M, Masson F, Miasari M, Belz GT, Smyth GK, Busslinger M, Nutt SL, Kallies A. The transcription factors Blimp-1 and IRF4 jointly control the differentiation and function of effector regulatory T cells. Nature Immunology. 2011, 12(4):304-311.
Research interests
Dr Belz’s research is predominantly focused on understanding how a subset of white blood cells, cytotoxic T cells (CTL, or CD8 T cells), recognise and remove virally-infected cells from the body following infection. The aim is to identify specific factors that determine how virus-specific killer T cells develop during an infection and how they impact on the establishment of immune memory after virus infection.
Dr Cretney’s research is predominantly focussed on understanding the regulation and function of a group of white blood cells, regulatory T (Treg) cells. Treg cells are absolutely essential to balance immune responses. They function by suppressing or blocking immune system activity and play an important role in maintaining self-tolerance, making sure that the immune system does not mount a response against our own (self) tissue.
Selected publications
- Jackson JT, Hu Y, Liu R, Masson F, D'Amico A, Carotta S, Xin A, Camilleri MJ, Mount AM, Kallies A, Wu L, Smyth GK, Nutt SL, Belz GT. Id2 expression delineates differential checkpoints in the genetic program of CD8α+ and CD103+ dendritic cell lineages. EMBO J. 2011 May 17;30(13):2690-704. PMID: 21587207
- Masson F, Kupresanin F, Mount A, Strasser A, Belz GT. Bid and Bim collaborate during induction of T cell death in persistent infection. J Immunol. 2011 186(7):4059-66. PMID: 21339359
- Belz GT, Kallies A. Effector and memory CD8+ T cell differentiation: toward a molecular understanding of fate determination. Curr Opin Immunol. 2010 Jun;22(3):279-85. PMID: 20434894
- Carotta S, Pang SH, Nutt SL, Belz GT. Identification of the earliest NK-cell precursor in the mouse BM. Blood. 2011 May 19;117(20):5449-52. PMID: 2142247
- Kallies A, Xin A, Belz GT, Nutt SL. Blimp-1 transcription factor is required for the differentiation of effector CD8+ T cells and memory responses. Immunity. 2009 21;31(2):283-95. PMID: 19664942
Research theme
Chronic inflammatory diseases
Scientific discipline
- Immunology
Keywords
Regulatory T cells, transcription factors, immunity, immune protection, intestinal homeostasis, innate immune cells.