Modeling T cell antigen discrimination based on feedback control of digital ERK responses.
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.
Altan-Bonnet
Grégoire
G
Lymphocyte Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland, United States of America.
Germain
Ronald N
RN
D000818:Animals; D000938:Antigen-Presenting Cells; D000941:Antigens / Q000737:chemistry; D000945:Antigens, Differentiation, T-Lymphocyte / Q000737:chemistry*; D002138:Calibration; D002454:Cell Differentiation; D002462:Cell Membrane / Q000378:metabolism; D016000:Cluster Analysis; D003198:Computer Simulation; D003593:Cytoplasm / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D025461:Feedback, Physiological; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007700:Kinetics; D008024:Ligands; D008213:Lymphocyte Activation; D008285:Major Histocompatibility Complex; D051379:Mice; D008822:Mice, Transgenic; D008962:Models, Theoretical; D010455:Peptides / Q000737:chemistry; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015203:Reproducibility of Results; D012190:Retroviridae / Q000378:metabolism; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D012984:Software; D013601:T-Lymphocytes / Q000378:metabolism; D018909:src Homology Domains
D000941:Antigens; D000945:Antigens, Differentiation, T-Lymphocyte; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D048049:Extracellular Signal-Regulated MAP Kinases; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C509248:Ptpn6 protein, mouse