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Abstract

T-cells play a key role within the immune system. Their importance is due to their capability to specifically recognize foreign, potentially dangerous agents and, subsequently, to initiate a specific immune response. T-cell reactivity must be precisely regulated: not only a decrease (which weakens the defenses), but also an increase (which can lead to autoimmune deseases) can have severe consequencies for the organism. Tcells detect foreign antigens by means of their T-cell receptor (TCR) which recognizes peptides bound to a protein complex called MHC. Binding of antigen triggers several signaling processes, among them, the activation of the MAPK cascade. We performed quantitative measurements of activation levels of key proteins upon different stimuli (CD3+CD8 antibodies and the more physiological tetramers) in primary splenic T-cells from transgenic mice using western blotting. Interestingly, antibody stimulation produces a rapid and strong activation of the cascade, leading to a transient activation of ERK and low proliferation, while tetramers activate the cascade in a weaker manner, producing sustained ERK activation and vigorous proliferation. This data suggests that the strong signals mediated by CD3/CD8-antibodies initiate regulatory mechanisms to prevent inappropriate T-cell activation. In order to identify and analyze the mechanism responsible for the observed dynamics, we set up detailed and mechanistic models including different plausible regulatory mechanisms. The models are constructed in a modular domain-oriented manner using ProMoT. The ability of the different models to reproduce the data is analyzed, obtaining insights into the regulation of the TCR induced MAPK cascade.