Mechanisms of chemokine and antigen-dependent T-lymphocyte navigation.
T-lymphocyte trafficking is targeted to specific organs by selective molecular interactions depending on their differentiation and functional properties. Specific chemokine receptors have been associated with organ-specific trafficking of memory and effector T-cells, as well as the recirculation of naïve T-cells to secondary lymphoid organs. In addition to the acquisition of tissue-selective integrins and chemokine receptors, an additional level of specificity for T-cell trafficking into the tissue is provided by specific recognition of antigen displayed by the endothelium involving the TCRs (T-cell antigen receptors) and co-stimulatory receptors. Activation of PI3K (phosphoinositide 3-kinase) is a robust signalling event shared by most chemokine receptors as well as the TCR and co-stimulatory receptors, contributing to several aspects of T-lymphocyte homing as well as actin reorganization and other components of the general migratory machinery. Accordingly, inhibition of PI3K has been considered seriously as a potential therapeutic strategy by which to combat various T-lymphocyte-dependent pathologies, including autoimmune and inflammatory diseases, as well as to prevent transplant rejection. However, there is substantial evidence for PI3K-independent mechanisms that facilitate T-lymphocyte migration. In this regard, several other signalling-pathway components, including small GTPases, PLC (phospholipase C) and PKC (protein kinase C) isoforms, have also been implicated in T-lymphocyte migration in response to chemokine stimulation. The present review will therefore examine the PI3K-dependent and -independent signal-transduction pathways involved in T-cell migration during distinct modes of T-cell trafficking in response to either chemokines or the TCR and co-stimulatory molecules.
Ward
Stephen G
SG
Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK. S.G.Ward@bath.ac.uk
Marelli-Berg
Federica M
FM
D000818:Animals; D000941:Antigens / Q000276:immunology*; D002465:Cell Movement / Q000276:immunology*; D018925:Chemokines / Q000276:immunology*; D006801:Humans; D009928:Organ Specificity / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000145:classification / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology*
D000941:Antigens; D018925:Chemokines; D019869:Phosphatidylinositol 3-Kinases