TY  - GEN
KW  - natural killer cells 
KW  -  signal transduction 
KW  -  cytotoxicity 
KW  -  immunology
ID  - heidok9974
AV  - public
Y1  - 2009///
TI  - Molecular analysis of the decision making process in NK cells
N2  - Natural killer (NK) cells are a subpopulation of lymphocytes that are involved in the control of different tumors and infections. Unlike T and B cells, NK cells belong to the innate part of the immune system. NK cells carry on their surface a multitude of activating and inhibitory receptors. The regulation of NK cell activation depends on a balance of positive and negative signals initiated by various receptors. Triggering of activating receptors leads to Src family kinase mediated Vav1 phosphorylation, whereas inhibitory receptors dephosphorylate Vav1 via the phosphatase SHP-1. This makes Vav1 the first point where negative signals can intercept the activating signaling cascade. In cooperation with computational biologists we established a mathematical model describing these early signaling events to gain insight into the integration of positive and negative signals on a molecular level. In quantitative mathematical models each equation refers to identifiable processes and parameters have physical interpretation (such as concentration, binding affinity and reaction rate). Therefore we quantified the concentrations of involved molecules. The predictions from the model and our experimental data show that engagement of activating receptors results in a rapid switch-like increase of Vav1 phosphorylation. Similarly, engagement of inhibitory receptors induces a switch-like dephosphorylation of Vav1 that is dominant over activating signals. Comparing experimental results to predictions derived from a family of simplified models shows that kinase association with the NK cell receptors and the enhanced activity of SHP-1 bound to inhibitory receptors is essential to simulate such a physiological response. Interestingly, other concepts of immune receptor signaling such as phosphatase segregation and kinase autophosphorylation were dispensable for our model. The cytotoxic activity of NK cells induced by a combination of activating and inhibitory signals correlates with the switch-like Vav1 phosphorylation. Our data are consistent with a central role of Vav1 in the decision making process of NK cells and enable a novel insight into the integration of positive and negative signals during lymphocyte activation.
A1  - Urlaub, Doris
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/9974/
ER  -