University of Dundee

Professor Colin Watts FRS FRSE FMedSci

The Cell Biology of the Immune System
Position: 
Professor of Immunobiology
Address: 
School of Life Sciences, University of Dundee, Dundee
Full Telephone: 
+44 (0) 1382 384233, int ext 84233
Email: 

Research

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.

Publications

Freeley, S, Cardone, J, Günther, SC, West, EE, Reinheckel, T, Watts, C, Kemper, C & Kolev, MV 2018, 'Asparaginyl endopeptidase (Legumain) supports human Th1 induction via cathepsin L-mediated intracellular C3 activation' Frontiers in Immunology, vol. 9, 2449, pp. 1-7. https://doi.org/10.3389/fimmu.2018.02449

Martinez-Fabregas, J, Prescott, A, van Kasteren, S, Leslie Pedrioli, D, McLean, W, Moles, A, Reinheckel, T, Poli, V & Watts, C 2018, 'Lysosomal protease deficiency or substrate overload induces an oxidative-stress mediated STAT3-dependent pathway of lysosomal homeostasis' Nature Communications, vol. 9, no. 1, 5343, pp. 1-16. https://doi.org/10.1038/s41467-018-07741-6

Stathopoulou, C, Gangaplara, A, Mallett, G, Flomerfelt, FA, Liniany, LP, Knight, D, Samsel, LA, Berlinguer-Palmini, R, Yim, JJ, Felizardo, TC, Eckhaus, MA, Edgington-Mitchell, L, Martinez-Fabregas, J, Zhu, J, Fowler, DH, van Kasteren, SI, Laurence, A, Bogyo, M, Watts, C, Shevach, EM & Amarnath, S 2018, 'PD-1 Inhibitory Receptor Downregulates Asparaginyl Endopeptidase and Maintains Foxp3 Transcription Factor Stability in Induced Regulatory T Cells' Immunity, vol. 49, no. 2, pp. 247-263.e7. https://doi.org/10.1016/j.immuni.2018.05.006

Matthews, SP, McMillan, SJ, Colbert, JD, Lawrence, RA & Watts, C 2016, 'Cystatin F Ensures Eosinophil Survival by Regulating Granule Biogenesis' Immunity, vol. 44, no. 4, pp. 795-806. https://doi.org/10.1016/j.immuni.2016.03.003

Zaru, R, Edgar, AJ, Hanauer, A & Watts, C 2015, 'Structural and functional basis for p38-MK2 activated Rsk signalling in Toll-Like receptor-stimulated dendritic cells' Molecular and Cellular Biology, vol. 35, no. 1, pp. 132-140. https://doi.org/10.1128/MCB.00773-14

Zaru, R, Matthews, SP, Edgar, AJ, Prescott, AR, Gomez-Nicola, D, Hanauer, A & Watts, C 2015, 'The PDK1-Rsk signaling pathway controls Langerhans cell proliferation and patterning' Journal of Immunology, vol. 195, no. 9, pp. 4264-4272. https://doi.org/10.4049/jimmunol.1501520

Gawden-Bone, C, West, MA, Morrison, VL, Edgar, AJ, McMillan, SJ, Dill, BD, Trost, M, Prescott, A, Fagerholm, SC & Watts, C 2014, 'A crucial role for β2 integrins in podosome formation, dynamics and Toll-like-receptor-signaled disassembly in dendritic cells' Journal of Cell Science, vol. 127, no. 19, pp. 4213-4224. https://doi.org/10.1242/jcs.151167

Maher, K, Konjar, S, Watts, C, Turk, B & Kopitar-Jerala, N 2014, 'Cystatin F regulates proteinase activity in IL-2-activated natural killer cells' Protein and Peptide Letters, vol. 21, no. 9, pp. 957-965. https://doi.org/10.2174/0929866521666140403124146

Morrison, VL, James, MJ, Grzes, K, Cook, P, Glass, DG, Savinko, T, Lek, HS, Gawden-Bone, C, Watts, C, Millington, OR, MacDonald, AS & Fagerholm, SC 2014, 'Loss of beta2-integrin-mediated cytoskeletal linkage reprogrammes dendritic cells to a mature migratory phenotype' Nature Communications, vol. 5, 5359. https://doi.org/10.1038/ncomms6359

Edgar, AJ, Trost, M, Watts, C & Zaru, R 2013, 'A combination of SILAC and nucleotide acyl phosphate labelling reveals unexpected targets of the Rsk inhibitor BI-D1870' Bioscience Reports. https://doi.org/10.1042/BSR20130094

Cuadrado, E, Jansen, MH, Anink, J, De Filippis, L, Vescovi, AL, Watts, C, Aronica, E, Hol, EM & Kuijpers, TW 2013, 'Chronic exposure of astrocytes to interferon-alpha reveals molecular changes related to Aicardi-Goutieres syndrome' Brain, vol. 136, no. 1, pp. 245-258. https://doi.org/10.1093/brain/aws321

Lek, HS, Morrison, VL, Conneely, M, Campbell, PA, McGloin, D, Kliche, S, Watts, C, Prescott, A & Fagerholm, SC 2013, 'The spontaneously adhesive leukocyte function-associated antigen-1 (LFA-1) integrin in effector T cells mediates rapid actin- and calmodulin-dependent adhesion strengthening to ligand under shear flow' Journal of Biological Chemistry, vol. 288, no. 21, pp. 14698-14708. https://doi.org/10.1074/jbc.M112.430918

Zou, F, Schmon, M, Sienczyk, M, Grzywa, R, Palesch, D, Boehm, BO, Sun, ZL, Watts, C, Schirmbeck, R & Burster, T 2012, 'Application of a novel highly sensitive activity-based probe for detection of cathepsin G' Analytical Biochemistry, vol. 421, no. 2, pp. 667-72. https://doi.org/10.1016/j.ab.2011.11.016

Magister, Š, Obermajer, N, Mirković, B, Švajger, U, Renko, M, Softić, A, Romih, R, Colbert, JD, Watts, C & Kos, J 2012, 'Regulation of cathepsins S and L by cystatin F during maturation of dendritic cells' European Journal of Cell Biology, vol. 91, no. 5, pp. 391-401. https://doi.org/10.1016/j.ejcb.2012.01.001

Watts, C 2012, 'The endosome-lysosome pathway and information generation in the immune system' Biochimica et Biophysica Acta. Proteins and Proteomics, vol. 1824, no. 1, pp. 14-21. https://doi.org/10.1016/j.bbapap.2011.07.006

van Kasteren, SI, Berlin, I, Colbert, JD, Keane, D, Ovaa, H & Watts, C 2011, 'A Multifunctional Protease Inhibitor To Regulate Endolysosomal Function' ACS Chemical Biology, vol. 6, no. 11, pp. 1198-1204. https://doi.org/10.1021/cb200292c

Miller, G, Matthews, SP, Reinheckel, T, Fleming, S & Watts, C 2011, 'Asparagine endopeptidase is required for normal kidney physiology and homeostasis' FASEB Journal, vol. 25, no. 5, pp. 1606-1617. https://doi.org/10.1096/fj.10-172312

Colbert, JD, Matthews, SP, Kos, J & Watts, C 2011, 'Internalization of Exogenous Cystatin F Supresses Cysteine Proteases and Induces the Accumulation of Single-chain Cathepsin L by Multiple Mechanisms' Journal of Biological Chemistry, vol. 286, no. 49, pp. 42082-42090. https://doi.org/10.1074/jbc.M111.253914

Gawden-Bone, C, Zhou, Z, King, E, Prescott, A, Watts, C & Lucocq, J 2010, 'Dendritic cell podosomes are protrusive and invade the extracellular matrix using metalloproteinase MMP-14' Journal of Cell Science, vol. 123, no. 9, pp. 1427-1437. https://doi.org/10.1242/jcs.056515

Matthews, SP, Werber, I, Deussing, J, Peters, C, Reinheckel, T & Watts, C 2010, 'Distinct Protease Requirements for Antigen Presentation In Vitro and In Vivo' Journal of Immunology, vol. 184, no. 5, pp. 2423-2431. https://doi.org/10.4049/jimmunol.0901486

Mattock, KL, Gough, PJ, Humphries, J, Burnand, K, Patel, L, Suckling, KE, Cuello, F, Watts, C, Gautel, M, Avkiran, M & Smith, A 2010, 'Legumain and cathepsin-L expression in human unstable carotid plaque' Atherosclerosis, vol. 208, no. 1, pp. 83-89. https://doi.org/10.1016/j.atherosclerosis.2009.07.022

Watts, C, West, MA & Zaru, R 2010, 'TLR signalling regulated antigen presentation in dendritic cells' Current Opinion in Immunology, vol. 22, no. 1, pp. 124-130. https://doi.org/10.1016/j.coi.2009.12.005