hThe initiation of signaling in T lymphocytes in response to the binding of the T cell receptor (TCR) to cognate ligands is a key step in the emergence of adaptive immune responses. Conventional models posit that TCR signaling is initiated by the phosphorylation of receptor-associated immune receptor activation motifs (ITAMs). The cytoplasmic tyrosine kinase Zap70 binds to phosphorylated ITAMs, is subsequently activated, and then propagates downstream signaling. While evidence for such models is provided by experiments with cell lines, in vivo, Zap70 is bound to phosphorylated ITAMs in resting T cells. However, Zap70 is activated only upon TCR binding to cognate ligand. We report the results of computational studies of a new model for the initiation of TCR signaling that incorporates these in vivo observations. Importantly, the new model is shown to allow better and faster TCR discrimination between self-ligands and foreign ligands. The new model is consistent with many past experimental observations, and experiments that could further test the model are proposed.T lymphocytes (T cells) play an important role in coordinating immune responses to infectious pathogens. They express T cell antigen receptor (TCR) molecules on their surfaces, which can recognize peptides bound to major histocompatibility complex (pMHC) molecules that are displayed on the surfaces of infected, or antigen-presenting, cells. Sufficiently strong binding of the TCR to peptide-MHC molecules can initiate TCR signaling, which is a key step in T cell activation and the development of adaptive immune responses.Peptides derived from both the host proteome and pathogenic proteins can bind to MHC molecules and can be expressed on the surface of a cell. It is critical that productive TCR signaling resulting in T cell activation be initiated when pathogenic pMHC molecules (agonists) are encountered. T cells discriminate between self-peptides and pathogenic peptides with high specificity and are extraordinarily sensitive to minute amounts of agonists (1). Much effort has been devoted to understanding the cellular machinery and topology of the membrane-proximal signaling network that enables T cells to exhibit these properties (2).Because of processes that occur during development of T cells in the thymus, TCRs expressed on mature T cells bind weakly to some self-peptide-MHC molecules present on peripheral tissues and antigen-presenting cells. These weak interactions generate some signaling necessary for homeostasis and T cell survival but are insufficient to initiate a full activation response by the T cell. Full activation of the T cell requires a more complete and stronger signal to initiate a cellular response. Although the details of the molecular mechanisms differ, most postulated mechanisms for the ability of TCR signaling to discriminate between agonists and self-ligands are variants of Hopfield's kinetic-proofreading idea, which was first adapted for T cells by Hopfield and McKeithan (3,4). In brief, one posits that a set of biochemical trans...

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We study a model of dynamic disorder relevant for signal transduction pathways in which enzymatic reaction rates fluctuate over several orders of magnitude. For the simple networks we consider, dynamic disorder drives the system far from equilibrium and imposes an energetic burden for high fidelity signaling capability. We study how the dynamics of the underlying stochastic behavior in the reaction rate process is related to the energetic cost of transmitting information through the network.