A logical analysis of the process of T cell activation: different consequences depending on the state of CD28 engagement.
The adaptive immune system is a complex organized action of several immune cell types like, T cells, B cells, dendritic cells, mast cells, and their ability to recognize self and foreign molecular information. Based on logical analysis, a model has been developed that describes TCR-ligand association coupled to intracellular signaling events that result in a proliferation signal. The model demonstrates that after TCR-ligand binding, the activation of tyrosine kinases in one of the paths leads to oscillations between the subsequent states of activation and deactivation of Ca(2+) initiation. In our studies the effect of costimulation on the primary signal has also been explored. Analysis reveals that costimulation increases by more than 2.5 fold the number of paths rendering a cell proliferation signal compared to the outcome when costimulation is blocked. Traversal of 97% of these paths attains a costimulation threshold of activation. We also examined a hypothesis that couples the primary signal and costimulation by modeling costimulation to act as an inhibitor on the Inhibitor proteins. Using this hypothesis our analysis showed a 25% increase in the number of paths leading to cell proliferation in comparison to when costimulation is blocked. Our model also reveals that this hypothesis actually decrease by approximately 50% the number of paths attaining cell proliferation compared to the number of available paths leading to cell proliferation when costimulation does not act as an inhibitor on Inhibitor proteins. This suggests that costimulation influences cell proliferation by providing a greater diversity of paths that converge to this state. However, costimulation should be thought independent of its regulatory interaction with the inhibitor proteins.
Sarkar
A
A
Cell Systems Initiative, Bioengineering, University of Washington, Seattle, WA 98195-8070, USA. sarkara@u.washington.edu
Franza
B R
BR
D018106:CD28 Antigens / Q000276:immunology*; D002455:Cell Division / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D018448:Models, Immunological; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D018106:CD28 Antigens; D011948:Receptors, Antigen, T-Cell