Tissue antigen and immune cell turnover in health and disease

A healthy immune system is in a state of restful homeostasis. Activation of the immune system, whether to fight infections or during immune-mediated diseases, involves substantial changes in the rates at which immune cells and proteins are produced and destroyed (turnover). Interestingly, immune activation can entail an increase in turnover of some immune components (e.g., very rapid proliferation and death of antigen-stimulated lymphocytes during an infection), whereas the turnover of other components is decreased (e.g., the reduced turnover of Human Leukocyte Antigens, or HLA molecules, in antigen-presenting cells after stimulation with microbial products). Knowledge of these rates is important in understanding healthy immune function, dysfunction, and ageing, and in the development of novel therapies, but they have been difficult to measure. The technical challenges of measurement are considerable, not least because turnover in the immune system is heterogeneous. Examples include the different turnover rates of memory T-cell subsets and of different HLA gene products in various antigen-presenting cell types.

Dr Busch has made important contributions to the biochemistry and cell biology of HLA molecules, which present peptide antigens to T cells of the adaptive immune system. He also has pioneered the development of techniques that use stable isotope labelling and mass spectrometry in order to quantify the rates of cell and protein turnover [1,2], with applications ranging from cultured cell lines to human patients. This PhD project will contribute to the further improvement of these techniques, and apply them to the dissection of cellular and molecular heterogeneity in host/pathogen interactions or autoimmune diseases. The specific research focus will be shaped according to the interests of the applicant; recent and continuing projects have included:

1) The effect of genetic diversity on the turnover of HLA antigens and their mouse homologues in antigen-presenting cells, in relation to their genetic associations with autoimmunity (collaborations with Hill Gaston and Anne Cooke, University of Cambridge, and with the Cambridge Centre for Proteomics) [3-5];

2) The role of specific proteases and peptide loading in determining the turnover of HLA class II antigens;

3) Influences of vitamin D and retinoic acid on the codominant expression and fate of HLA class II antigens in cultured antigen-presenting cells (with the Cambridge Centre for Proteomics);

4) The effect of KIR/HLA interactions on the turnover of CD8+ T cells and NK cells in patients with chronic viral infection (collaboration with Derek Macallan, St George’s, University of London, and Becca Asquith, Imperial College London);

5) The automation of methods for measuring cell turnover using lab-on-a-chip devices, in conjunction with the development of single-cell measurements of proliferative fate by heavy water labelling of DNA (collaboration with the Department of Engineering, University of Cambridge).

The successful applicant will have Bachelor’s and Master’s qualifications in relevant degree subjects, laboratory experience with an emphasis on quantitative molecular techniques preferred, and interests in assay development and in the immune system. Co-supervision, training, and collaborative arrangements will be made with consideration of the applicant’s specific research focus and learning needs.

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