T cells have a central role in the bodys immune response to pathogens and other disorders such as in cancer and autoimmune disorders. T cells are constantly moving and this migration involves the interactions of different adhesion molecules such as the integrins. One important member of this family is the integrin LFA-1. When this integrin binds to its ligand ICAM-1, it has an adhesive function but it also has a key role in signalling. The Hogg lab has shown that the binding of LFA-1 to ICAM-1 signals reorganisation of the cytoskeleton and motility in the T cell. In fibroblasts and endothelial cells, the regulation of integrin-containing adhesions is dependent on a Ca2+-requiring cysteine protease called calpain. The Hogg lab has demonstrated that calpain is involved in formation of the LFA-1-mediated adhesions made by T cells and that it has a specific role in the de-adhesion of the migrating T cell. The applicant has evidence that the activation of calpain is dependent on the G protein heterodimer G12/13 an d also on phospholipase C which can give rise to the Ca2+ flux necessary for calpain activity. The aim of the proposed project is to identify the individual signalling pathway members leading from G12/13 to active calpain and, secondly, to understand how they affect T cell migration. Briefly we will identify the downstream elements from G12/13 and we will first investigate the role of GTPase Rho and its major effector Rho kinase and also the role of PLCepsilon. Importantly, we will link these findings to a lteration of T cell migration and look in more detail at specific alteration of LFA-1 adhesions. T cells spend most of their lives either circulating in and out of lymph nodes as naïve cells or, following exposure to antigen, migrating into other tissues. Therefore it is of great importance to understand the mechanisms behind this migration and ultimately to offer the possibility of intervention in patients with abnormal immune responsiveness.
Field of science
- /medical and health sciences/health sciences/public and environmental health/epidemics prevention/immunisation
Call for proposal
See other projects for this call