Professor Colin Watts FRS FRSE FMedSci
The cell biology of the immune response
Dendritic cells (DC) collaborate with T cells to initiate immune responses and do so by capturing antigen, processing it within compartments of the endo/lysosome system and creating peptide/MHC complexes that are returned to the cell surface for scrutiny by T cells. Superimposed on this are the events of DC migration which requires crossing of cell and matrix barriers to bring DC together with T cells in lymphoid organs. Our lab is interested in the cell biology of DC at the early stages of this response, in the events of antigen processing and presentation and more generally in endo/lysosomal proteases and their regulation in immune cells.
We are studying the acute responses that DC make to microbial products, particularly how they are signaled by MAP kinase pathways and how they affect the cytoskeleton. We are testing new approaches to manipulate how antigens and vaccines are processed in antigen presenting cells. Evidence from our lab and others suggests, somewhat counter intuitively, that reducing their susceptibility to processing might improve the performance of some vaccines. Proteases are often regulated by protease inhibitors and we are studying an unusual protease inhibitor called cystatin F or leukocystatin that is almost exclusively expressed in immune cells. Cystatin F is made in an inactive dimer form and activated by proteolysis. This very distinct mode of activation suggests that cystatin F may protect cells from excessive lysosomal protease activity and its consequences.
- Matthews, S. P., McMillan, S. J., Colbert, J. D., Lawrence, R. A. and Watts, C. (2016) Cystatin F Ensures Eosinophil Survival by Regulating Granule Biogenesis. Immunity. 44, 795-806
- Zaru, R., Matthews, S. P., Edgar, A. J., Prescott, A. R., Gomez-Nicola, D., Hanauer, A. and Watts, C. (2015) The PDK1-Rsk Signaling Pathway Controls Langerhans Cell Proliferation and Patterning. J Immunol. 195, 4264-4272
- Zaru, R., Edgar, A. J., Hanauer, A. and Watts, C. (2015) Structural and functional basis for p38-MK2-activated Rsk signaling in toll-like receptor-stimulated dendritic cells. Mol Cell Biol. 35, 132-140
- Gawden-Bone, C., West, M. A., Morrison, V. L., Edgar, A. J., McMillan, S. J., Dill, B. D., Trost, M., Prescott, A., Fagerholm, S. C. and Watts, C. (2014) A crucial role for beta2 integrins in podosome formation, dynamics and Toll-like-receptor-signaled disassembly in dendritic cells. J Cell Sci. 127, 4213-4224
- Edgar, A. J., Trost, M., Watts, C. and Zaru, R. (2013) A combination of SILAC and nucleotide acyl phosphate labelling reveals unexpected targets of the Rsk inhibitor BI-D1870. Bioscience reports10.1042/BSR20130094
- Watts, C. (2012) The endosome-lysosome pathway and information generation in the immune system. Biochimica et biophysica acta. 1824, 14-21
- Miller, G., Matthews, S. P., Reinheckel, T., Fleming, S. and Watts, C. (2011) Asparagine endopeptidase is required for normal kidney physiology and homeostasis. Faseb J. 25, 1606-1617
- van Kasteren, S. I., Berlin, I., Colbert, J. D., Keane, D., Ovaa, H. and Watts, C. (2011) A multifunctional protease inhibitor to regulate endolysosomal function. ACS Chem Biol. 6, 1198-1204
- Colbert, J. D., Matthews, S. P., Kos, J. and Watts, C. (2011) Internalization of exogenous cystatin F supresses cysteine proteases and induces the accumulation of single-chain cathepsin L by multiple mechanisms. J Biol Chem. 286, 42082-42090
- Matthews, S. P., Werber, I., Deussing, J., Peters, C., Reinheckel, T. and Watts, C. (2010) Distinct protease requirements for antigen presentation in vitro and in vivo. J Immunol. 184, 2423-2431