Close
Supervisors: Professor Lucy Wedderburn, Dr Kiran Nistala, Dr David Bending
A key task of the healthy immune system is to prevent autoimmune diseases like arthritis, during which immune cells attack the body. A key cell to maintain this immune 'tolerance' is the regulatory T cell, which can be identified by the fact that they express a protein called Foxp3. We have recently found that some Foxp3 Treg also make inflammatory molecules (cytokines), even though they still express Foxp3. We call these the Jekyll and Hyde Treg.
We have studied these cells in children with arthritis (also called juvenile idiopathic arthritis or JIA). A large number of children with JIA attend Great Ormond Street hospital, which gives us a unique chance to study how their immune tolerance works, or why it fails. We can find the Jekyll and Hyde Treg cells in the blood, and even more of them in the joint, of children with arthritis - they can be distinguished from other Treg cells because they express a marker called CD161. We have now generated exciting new data that tell us some key differences in the programme of gene expression between CD161 Treg and the CD161 negative Treg cells.
In this PhD the student will address three novel and important questions:
1. Do Treg of the CD161 and CD161- populations supress immune responses through
the same or different mechanisms? If different, can we manipulate these differences
to design new treatments for arthritis?
2. Can signalling differences between these two types of regulatory cell be exploited,
to make these Treg cells suppress arthritis more effectively?
3. Would depletion of CD161+ Treg cells in the laboratory, during the preparation of
Treg to give to patients, generate a more effective cellular therapy for clinical use in
patients?
Through this PhD the student will have an excellent training in molecular and cellular
Immunology
as well as learn to test manipulate and understand the key signalling
and functional pathways important to immune tolerance. In addition
he/she will have a first hand exposure to translational science,
including an understanding of the development of new biomarkers and
therapies, as well as opportunities to meet the children/young people
and families, who this project aims to benefit.
References:
1. de Kleer, I.M., et al., CD4+CD25(bright) regulatory T cells actively regulate
inflammation
in the joints of patients with the remitting form of juvenile
idiopathic arthritis. J Immunol, 2004. 172(10): p. 6435-43.
2. Nistala, K., et al., Interleukin-17-producing T cells are enriched in the joints of
children with arthritis, but have a reciprocal relationship to regulatory T cell numbers.
Arthritis Rheum, 2008. 58(3): p. 875-87.
3. Pesenacker, A.M., et al., CD161 defines the subset of FoxP3+ T cells capable of
producing proinflammatory cytokines. Blood, 2013. 121(14): p. 2647-58.
4. Nistala, K., et al., Th17 plasticity in human autoimmune arthritis is driven by the
inflammatory environment. Proc Natl Acad Sci U S A, 2010. 107(33): p. 14751-6.
5. McFarlane, L.A., and Todd, D. J. Kinase inhibitors: The next generation of therapies
in the treatment of rheumatoid arthritis. Int J Rheum Dis, 2014. 17: 359-368
