Modeling T cell antigen discrimination based on feedback control of digital ERK responses.
TLDR
In this article, the authors constructed a new mathematical model of proximal TCR-dependent signaling and found 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.Abstract:
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 × 105–1 × 106 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.read more
Citations
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miR-181a is an intrinsic modulator of T cell sensitivity and selection
Qi-Jing Li,Jacqueline Chau,Peter J.R. Ebert,Giselle Sylvester,Hyeyoung Min,Gwen Liu,Ravi Braich,Muthiah Manoharan,Juergen Soutschek,Petra Skare,Lawrence O. Klein,Mark M. Davis,Chang-Zheng Chen +12 more
TL;DR: It is shown that increasing miR-181a expression in mature T cells augments the sensitivity to peptide antigens, while inhibition in the immature T cells reduces sensitivity and impairs both positive and negative selection.
Journal ArticleDOI
T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition.
Enfu Hui,Jeanne Cheung,Jing Zhu,Xiaolei Su,Marcus J. Taylor,Heidi J.A. Wallweber,Dibyendu Kumar Sasmal,Jun Huang,Jeong M. Kim,Ira Mellman,Ronald D. Vale +10 more
TL;DR: It is shown that the co-receptor CD28 is strongly preferred over the TCR as a target for dephosphorylation by PD-1–recruited Shp2 phosphatase, suggesting that costimulatory pathways play key roles in regulating effector T cell function and responses to anti-PD-L1/PD-1 therapy.
Journal ArticleDOI
Accumulation of Dynamic Catch Bonds between TCR and Agonist Peptide-MHC Triggers T Cell Signaling
TL;DR: The data support a model in which force on the TCR induces signaling events depending on its magnitude, duration, frequency, and timing, such that agonists form catch bonds that trigger the T cell digitally, whereas antagonists form slip bonds that fail to activate.
Journal ArticleDOI
Mechanisms for T cell receptor triggering
TL;DR: There is considerable controversy about the mechanism of T cell receptor triggering, the process by which the TCR tranduces signals across the plasma membrane after binding to its ligand (an agonist peptide complexed with an MHC molecule).
Journal ArticleDOI
Frequency-modulated pulses of ERK activity transmit quantitative proliferation signals.
TL;DR: Continuous response curves measured in multiple cell lines reveal that proliferation is effectively silenced only when ERK pathway output falls below a threshold of ~10%, indicating that high-dose targeting of the pathway is necessary to achieve therapeutic efficacy.
References
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Immunobiology: The Immune System in Health and Disease
TL;DR: Introductory immunology textbook for medical students, advanced undergraduates, and graduate students.
Journal ArticleDOI
The Immunological Synapse: A Molecular Machine Controlling T Cell Activation
Arash Grakoui,Shannon K. Bromley,Cenk Sumen,Mark M. Davis,Andrey S. Shaw,Paul M. Allen,Michael L. Dustin +6 more
TL;DR: Immunological synapse formation is now shown to be an active and dynamic mechanism that allows T cells to distinguish potential antigenic ligands and was a determinative event for T cell proliferation.
Journal ArticleDOI
T cell receptor antagonist peptides induce positive selection
Kristin A. Hogquist,Stephen C. Jameson,William R. Heath,Jane L Howard,Michael J. Bevan,Francis R. Carbone +5 more
TL;DR: Results show that the process of positive selection is exquisitely peptide specific and sensitive to extremely low ligand density and support the notion that low efficacy ligands mediate positive selection.
Journal ArticleDOI
RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement
Yoichi Shinkai,Gary Rathbun,Kong-Peng Lam,E. M. Oltz,Valerie Stewart,Monica Mendelsohn,Jean Charron,Milton Datta,Faith Young,Alan M. Stall,Frederick W. Alt +10 more
TL;DR: Loss of RAG-2 function in vivo results in total inability to initiate V(D)J rearrangement, leading to a novel severe combined immune deficient (SCID) phenotype.