Abstract
Activation of T lymphocytes by peptide/major histocompatibility complex on antigen-presenting cells (APCs) involves dynamic contacts between the two cells, during which T cells undergo marked morphological changes. These interactions are facilitated by integrins. Activation of the T cells increases the binding of the integrin lymphocyte function-associated antigen 1 (LFA-1) expressed by T cells to intercellular adhesion molecule (ICAM)-1 and ICAM-2 expressed by APCs. The signalling pathways that control integrin affinities are incompletely defined. The phosphoinositide 3-kinases (PI3Ks) generate second-messenger signalling molecules that control cell growth, proliferation, differentiation and trafficking. Here we show that in T cells, PI3Kδ attenuates the activation of Rac1, but sustains the activation of Rap1. Consequently, PI3Kδ increases LFA-1-dependent adhesion to form stable conjugates with APCs. Increased Rap1 activity and LFA-1 adhesion were only in part mediated by the downstream kinase Akt, suggesting the involvement of additional phosphatidylinositol(3,4,5)P3-binding proteins. These results establish a link between PI3K activity, cytoskeletal changes and integrin binding and help explain the impaired T-cell-dependent immune responses in PI3Kδ-deficient mice.
Highlights
Phosphoinositide 3-kinases (PI3Ks) catalyse the conversion of phosphatidylinositol(4,5)P2 to phosphatidylinositol(3,4,5)P3 (PIP3)
In the study we have investigated the effect of inhibiting PI3Kδ on the ability of CD4+ T cells to form productive conjugates with antigen-presenting cells (APCs)
This contrasts to observations in neutrophils where PI3K has been shown to positively regulate Rac activity via the protein P-Rex[1], which catalyses the exchange of GDP for GTP on Rac using its guanine exchange factors (GEFs) domain.[37]
Summary
Phosphoinositide 3-kinases (PI3Ks) catalyse the conversion of phosphatidylinositol(4,5)P2 to phosphatidylinositol(3,4,5)P3 (PIP3). PIP3 acts as a lipid second messenger by recruiting PH domain containing proteins to the plasma membrane where they activate signalling pathways that promote proliferation, differentiation, survival and chemotaxis.[1,2,3] The best understood PIP3 effector is the serine/ threonine kinase Akt, which inactivates Foxo transcription proteins, whereas increases mechanistic target of rapamycin kinase activity.[4,5] These pathways are evolutionary conserved and are thought to be responsible for many of the biological functions of PI3Ks. it has been estimated that there are up to 50 additional PIP3-binding proteins in the human genome and the function of many of these remain to be fully appreciated.[6] These include numerous guanine exchange factors (GEFs) and GTPase-activating proteins (GAPs) that positively and negatively regulate small GTPases.[7]. T cells to develop into Th1, Th2, Th17 or Tfh subsets; and production of effector cytokines.[10,11,12,13,14] PI3Kδ is required for the expression of certain adhesion and chemokine receptors and in antigen-dependent trafficking of T cells.[15,16,17]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
