Adaptive immune responses are highlyco-ordinated and rely upon efficient intracellular communication to orchestratecell function. Phosphoinositide 3-kinase (PI3K) signalling is a well-studiedand important positive mediator in T lymphocyte function; however the role for SH2-domaincontaining inositol phosphatase 1 (SHIP-1), a negative regulator of PI3Ksignalling, has not been so thoroughly investigated. The use of knockout mousemodels has given an insight into the role of SHIP-1 in murine T cells, butthese are compromised by loss of function during development which impingesupon mature T cell function and by the loss of non-catalytic functions ofSHIP-1. Recent work has indicated a clear rolefor reactive oxygen species (ROS), specifically hydrogen peroxide (H2O2),in immune cell signalling and functional responses including migration. Howeverlike SHIP-1, the functional roles of ROS are poorly understood in human Tlymphocytes, particularly the mechanisms by which ROS signals to alter Tlymphocyte biology. ROS has been previously shown to activate PI3K, Mitogenactivate protein kinase (MAPK) and Src family tyrosine kinase (SFK) signallingin a number of different cell types. In addition, ROS have been shown to inactivatephosphatase and tensin homology (PTEN), another negative regulator of PI3K, andare postulated to inactive SHIP-1 signalling. A pharmacological approach wasutilised to manipulate the catalytic activity of SHIP-1 and the cellularaccumulation of ROS in primary human T lymphocytes. Remarkably, it wasdetermined that both SHIP-1 activation and inhibition reduced the ligand-mediatedfunctions of human T lymphocytes, including signalling, proliferation, adhesionand migration. Furthermore, H2O2 selectively inhibited directionalmigration to chemokine CXCL11, enhanced F-actin polymerisation and decreasedactin polarisation to CXCL11. H2O2 required SFKsignalling to induce the phosphorylation/catalytic activation of SHIP-1 and todecrease the surface expression of CXCR3, both of which could be mechanismsunderlying the deficiency in migration observed with H2O2.
|Date of Award||4 Nov 2015|
|Supervisor||Stephen Ward (Supervisor), William Wood (Supervisor) & Malcolm Watson (Supervisor)|
- T Lymphocyte
- Oxidative signalling
- PI3K kinase