Science jobs from Babraham Institute: job description
A 4 year BBSRC CASE studentship is available to investigate the role of PI3K in T helper cell differentiation and cytokine secretion. To be eligible, you need to be a UK resident or EU national and to meet the criteria for dmission to the University of Cambridge Graduate School which include obtaining a first or upper second class BSc degree or equivalent. The ideal candidate will have a degree in biological sciences including a significant immunology component.
The student will also spend a proportion of the time at GSK in Stevenage. In addition, GSK will pay £3000 in addition to the standard BBSRC annual stipend. EU residents may need to apply for additional funding (see http://www.babraham.ac.uk/graduate/funding.htm for details).
Informal inquiries can be addressed to Dr Klaus Okkenhaug (klaus.okkenhaug@bbsrc.ac.uk).
Project description:
Regulation of T helper cell differentiation, cytokine expression and secretion by PI3K
CD4 helper T cells that have never been exposed to cognate antigens are referred to as naïve or virgin T cells. Naïve T cells require costimulation for their activation and can within hours produce the cytokine interleukin 2. Subsequently, and depending on cytokines present during the initial stimulation, naïve T cells differentiate to adopt effector phenotypes which are classified as distinct Th or regulatory T cell lineages based on the combination of transcription factors they express and the types of cytokines they can secrete. Initially, a simple model prevailed where T cells either differentiated to IFN-γ secreting Th1 cells or IL-4 secreting Th2 cells.
PI3Ks are intracellular lipid kinases that generate second messenger signalling molecules which control growth, proliferation, differentiation and migration. We have shown that p110δ(D910A) mice, in which the p110δ PI3K catalytic subunit has been inactivated by point mutation, are resistant to differentiate and produce less effector cytokines such as IL-4 or IFN-γ (Okkenhaug et al 2006; Patton et al 2007).
While the Th1/Th2 dichotomy model has been extremely useful in identifying the principles, signalling pathways, transcription factors and epigenetic changes that control T cell differentiation, the model has been wholly inadequate in explaining the complexity of immune responses to pathogens or how autoimmune diseases develop. We now know that naïve T cells can adopt at least 5 different well-defined lineages (Th1, Th2, Th17, Tfh and Treg) and more are likely to be discovered. The student will elucidate precise roles played by p110δ in regulating Th cell differentiation and cytokine expression, both by extending our previous observations and by investigating the effect of PI3K inhibition on the development of new Th subsets.
These studies should provide novel insights into how a conserved signalling pathway can be exploited by T cells to fine-tune immune responses against diverse pathogenic micro-organisms.
References
Okkenhaug, K., D. T. Patton, A. Bilancio, F. Garcon, W. C. Rowan, and B. Vanhaesebroeck. 2006. The p110δ Isoform of Phosphoinositide 3-Kinase Controls Clonal Expansion and Differentiation of Th Cells. J Immunol 177:5122-5128.
http://www.jimmunol.org/cgi/content/abstract/177/8/5122
Patton, D. T., F. Garcon, and K. Okkenhaug. 2007. The PI3K p110δ controls T-cell development, differentiation and regulation. Biochem Soc Trans 35:167-171.
http://www.biochemsoctrans.org/bst/035/bst0350167.htm
