Position: Professor of Immunobiology and Head of the Division of Cell Signalling and Immunology
Division: Cell Signalling and Immunology
Address: College of Life Sciences,
University of Dundee,
Dundee
Telephone: +44 1382 384233, int ext. 84233
Fax: +44 1382 385783
Email: c.watts@dundee.ac.uk
Website: Watts Lab
The adaptive immune response to a foreign microorganisms involves collaborations betweens different immune cell types. A key event is the activation of T lymphocytes by dendritic cells. Dendritic cells (DC) detect the presence of foreign invaders and communicate this information to the cells that will eventually eliminate the pathogen, for example, T & B lymphocytes. In vivo, DC travel from the site of infection to the lymphoid organs where initial interactions with T cells are possible. Dendritic cells are able to report on the nature of the pathogen and also capture pathogen-derived protein material which becomes broken down by proteases and ‘presented’ to T cells as short peptides bound to so called MHC molecules. It is this peptide/MHC complex which is recognised and acted on by T cells. Remarkably, immune tolerance to our own proteins seems also to involve a very similar recognition of peptide/MHC complexes by DC but in the absence of signals from pathogens.
We are working on the proteolytic enzymes that generate antigenic peptides for example, the cysteine and aspartic proteases found in endosomes and lysosomes. A conundrum here is that while some processing is clearly needed, too much will destroy the peptide products before they are captured by class II MHC molecules. We and others have found several examples of this and we are assessing the implications both for vaccine design and for effective tolerance to our own proteins. The need to regulate cysteine proteases is indicated by the existence of a family of endogenous inhibitors called cystatins. We are working on one family member, cystatin F, which is almost exclusively expressed in immune cells. Cystatin F may attenuate cysteine protease activity in T cells, NK cells and other several immune cell types.
We are investigating how DC capture antigens using mechanisms such as phagocytosis and macropinocytosis and how the configuration of the DC cytoskeleton and intracellular compartments is controlled by stimuli from pathogens. DC sense microbial pathogens using Toll-like receptors (TLRs) and other systems. We are particularly interested in acute responses triggered in DC within minutes of TLR activation. Some of these involve the actin cytoskeleton and include transiently enhanced endocytosis and the modulation of actin-rich structures called podosomes which are foci of matrix metalloprotease activity. We are working on how these responses are signalled and how podosomes might be involved in DC emigration from tissues.
The image shows dendritic cells stimulated with LPS in the presence of fluorescently labelled dextran (green). Endocytosis is increased several fold leading to the formation of large dextran-filled endosomes called macropinosomes. At the same time, actin-rich structures called podosomes transiently disappear but then return. The cell in the centre has retained its podosomes seen as red dots, whereas the other cells with many macropinosomes have lost theirs.
