Kennedy Trust Prize Studentships
The regulation of lymphocyte function by tryptophan catabolites
Catabolism of tryptophan along the kynurenine pathway yields a number of metabolites with important effects on cells of the immune system, including regulatory T cells and Th17 cells. The sites and mechanisms of action of these metabolites remain largely unexplored but include the aryl hydrocarbon receptor, glutamate receptors, and G-protein coupled receptor-35. In addition, the depletion of tryptophan by indoleamine 2,3-dioxygenase (IDO) results in inhibition of mTOR as well as by activation of the amino acid sensor, GCN2, which has profound immodulatory effects. The kynurenine pathway is thought to play an important role in inhibiting immune mediated inflammatory responses and in contributing to immune evasion in cancer.
This project will involve examination of T cell subset differentiation under resting conditions and on changing the cytokine milieu, with or without the addition of kynurenine or its catabolites kynurenic acid, 3-hydroxykynurenine (3HK), 3-hydroxy-anthranilic acid, anthranilic acid, quinolinic acid, picolinic acid and xanthurenic acid. In addition, the mechanisms by which the kynurenines affect T cell balance and function will be assessed by comparing their actions with ligands activating defined, recognised modulators of T cell function and by testing antagonists or using genetically modified animals at those sites to assess their importance as functional targets of the kynurenine catabolites.
Having analysed the effects of kynurenine catabolites on T cell proliferation and differentiation it will be important also to examine their effects on spontaneous and targeted migration. The project will also include an analysis of role of the kynurenine pathway in regulation of immune response in vivo. This will involve the utilisation of models of autoimmune disease and/or cancer.
The Kennedy Institute is a world-renowned research centre and is housed in a brand new state-of-the-art research facility. Full training will be provided in a range of cell and molecular biology techniques. A core curriculum of 20 lectures will be taken in the first term of year 1 to provide a solid foundation in musculoskeletal sciences, immunology and data analysis. Students will attend weekly departmental meetings and will be expected to attend seminars within the department and those relevant in the wider University. Subject-specific training will be received through our group's weekly supervision meetings. Students will also attend external scientific conferences where they will be expected to present the research findings.
- Cribbs AP, Kennedy A, Penn H, Read JE, Amjadi P, Green P, Syed K, Manka SW, Brennan FM Gregory B, Williams RO. Regulatory T cell function in rheumatoid arthritis is compromised by CTLA-4 promoter methylation resulting in a failure to activate the IDO pathway. Arthritis Rheumatol 2014; 66:2344-54.
- Stone TW, Stoy N, Darlington LG. An expanding range of targets for kynurenine metabolites of tryptophan. Trends Pharmacol Sci 2013; 3:136-43.
- Kolodziej LR, Paleolog EM, Williams RO. Kynurenine metabolism in health and disease. Amino Acids 2011;41:1173-83
- Criado G, Simelyte E, Inglis JJ, Essex D, Williams RO. IDO-mediated tryptophan catabolism regulates Th1/Th17-dependent joint inflammation in collagen-induced arthritis. Arthritis Rheum 2009; 60:1342-51.
- Immunology, musculoskeletal science, cancer, translational medicine and medical technology