Modeling T cell antigen discrimination based on feedback control of digital ERK responses

• Published in: PLoS biology 2005-11, Vol.3 (11), p.e356-e356
• Main Authors: Altan-Bonnet, Grégoire, Germain, Ronald N
• Format: Article
• Language: English
• Subjects: Animals; Antigen-Presenting Cells; Antigens - chemistry; Antigens, Differentiation, T-Lymphocyte - chemistry; Biochemistry; Bioinformatics/Computational Biology; Calibration; Cell Biology; Cell Differentiation; Cell Membrane - metabolism; Cluster Analysis; Computer Simulation; Cytoplasm - metabolism; Eukaryotes; Extracellular Signal-Regulated MAP Kinases - metabolism; Feedback, Physiological; Flow Cytometry; Gene Expression Regulation; Immunology; Intracellular Signaling Peptides and Proteins - metabolism; Kinases; Kinetics; Ligands; Lymphocyte Activation; Major Histocompatibility Complex; Mammals; Medical research; Mice; Mice, Transgenic; Models, Theoretical; Mus (Mouse); Peptides - chemistry; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Protein Tyrosine Phosphatases - metabolism; Proteins; Receptors, Antigen, T-Cell - metabolism; Reproducibility of Results; Retroviridae - metabolism; Sensitivity and Specificity; Signal Transduction; Software; src Homology Domains; Systems Biology; T cell receptors; T-Lymphocytes - metabolism; Vertebrates
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.0030356

T-lymphocyte activation displays a remarkable combination of speed, sensitivity, and discrimination in response to peptide-major histocompatibility complex (pMHC) ligand engagement of clonally distributed antigen receptors (T cell receptors or TCRs). Even a few foreign pMHCs on the surface of an antigen-presenting cell trigger effective signaling within seconds, whereas 1 x 10(5)-1 x 10(6) self-pMHC ligands that may differ from the foreign stimulus by only a single amino acid fail to elicit this response. No existing model accounts for this nearly absolute distinction between closely related TCR ligands while also preserving the other canonical features of T-cell responses. Here we document the unexpected highly amplified and digital nature of extracellular signal-regulated kinase (ERK) activation in T cells. Based on this observation and evidence that competing positive- and negative-feedback loops contribute to TCR ligand discrimination, we constructed a new mathematical model of proximal TCR-dependent signaling. The model made clear that competition between a digital positive feedback based on ERK activity and an analog negative feedback involving SH2 domain-containing tyrosine phosphatase (SHP-1) was critical for defining a sharp ligand-discrimination threshold while preserving a rapid and sensitive response. Several nontrivial predictions of this model, including the notion that this threshold is highly sensitive to small changes in SHP-1 expression levels during cellular differentiation, were confirmed by experiment. These results combining computation and experiment reveal that ligand discrimination by T cells is controlled by the dynamics of competing feedback loops that regulate a high-gain digital amplifier, which is itself modulated during differentiation by alterations in the intracellular concentrations of key enzymes. The organization of the signaling network that we model here may be a prototypic solution to the problem of achieving ligand selectivity, low noise, and high sensitivity in biological responses.