Coreceptor affinity for MHC defines peptide specificity requirements for TCR interaction with coagonist peptide–MHC

Hoerter, John A. H.; Brzostek, Joanna; Artyomov, Maxim N.; Abel, Steven M.; Casas, Javier; Rybakin, Vasily; Ampudia, Jeanette; Lotz, Carina; Connolly, Jennifer M.; Chakraborty, Arup K.; Gould, Keith G.; Gascoigne, Nicholas R. J.

doi:10.1084/jem.20122528

Cited by 29 publications

(66 citation statements)

References 56 publications

(133 reference statements)

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“…Stabilization of the active conformation of Lck promotes its ability to further phosphorylate other Lck molecules and Zap70 molecules associated with vicinal TCRs that are bound to other agonist or endogenous ligands, thereby generating a positive-feedback mechanism that could then overwhelm other, negative-feedback loops that maintain the resting state. By this means, our model is also in harmony with studies that suggest that signaling due to TCR-agonist pMHC ligands is amplified by endogenous pMHC molecules (6,7,23). The importance of Lck's SH2 domain for its function has also been emphasized by studies wherein CD4 coreceptor function was reconstituted in a Lck-sufficient antigen-specific hybridoma with CD4-Lck fusion proteins (17).…”

Section: Discussionsupporting

confidence: 67%

“…We estimate steady-state probability distributions of activated Zap70 when the network is stimulated by self-pMHC alone and then when a small percentage (2 to 4%) of agonist pMHC is also present. This is to mimic the fact that a very small number of agonist pMHC molecules can trigger T cell responses (1,(20)(21)(22)(23)(24)(25)(26). We carry out calculations over a wide range of values of the ratio of the dissociation rates of the TCR from self-pMHC and agonist (nonself-pMHC) ligands (k off,self /k off,nonself ) to assess the ability of the networks to discriminate between self and nonself.…”

Section: Resultsmentioning

confidence: 99%

“…Computational and experimental work has shown the kinetics of CD8 to play an important role in T cell discrimination (23,32). Because CD8 is now effectively bound to the complex, not only through its interaction with the pMHC, but also through the Lck-Zap70 bond, we expect that an important feature of this model is that the off rate of CD8 from a TCR-pMHC will be effectively lowered.…”

Section: Figmentioning

confidence: 99%

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Phosphorylation of a Tyrosine Residue on Zap70 by Lck and Its Subsequent Binding via an SH2 Domain May Be a Key Gatekeeper of T Cell Receptor Signaling In Vivo

Thill

Weiss

Chakraborty

2016

Molecular and Cellular Biology

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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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Section: Discussionsupporting

confidence: 67%

Section: Resultsmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

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Phosphorylation of a Tyrosine Residue on Zap70 by Lck and Its Subsequent Binding via an SH2 Domain May Be a Key Gatekeeper of T Cell Receptor Signaling In Vivo

Thill

Weiss

Chakraborty

2016

Molecular and Cellular Biology

Self Cite

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“…According to that model, it is only at later time points that CD8-bound LCK molecules interact with phosphorylated ZAP-70 molecules via their SH2 domain and stabilize TCR-pMHC interaction via their extracellular domain (94). In another model, the recognition of self-pMHC ligands is thought to facilitate TCR triggering because these serve as coagonists when a T cell encounters very low densities of agonist pMHC ligands (95,96). Some T cell clones and hybridomas kept in culture also can respond to agonist pMHC ligands irrespective of coreceptor expression, a finding that challenges models based on pMHC-induced heterodimerization of TCRs and coreceptors.…”

Section: Limits To Existing Tcr-triggering Modelsmentioning

confidence: 99%

Early T Cell Activation: Integrating Biochemical, Structural, and Biophysical Cues

Malissen

Bongrand

2015

Annu. Rev. Immunol.

121

114

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T cells carry out the formidable task of identifying small numbers of foreign antigenic peptides rapidly and specifically against a very noisy environmental background of endogenous self-peptides. Early steps in T cell activation have thus fascinated biologists and are among the best-studied models of cell stimulation. This remarkable process, critical in adaptive immune responses, approaches and even seems to exceed the limitations set by the physical laws ruling molecular behavior. Despite the enormous amount of information concerning the nature of molecules involved in the T cell antigen receptor (TCR) signal transduction network, and the description of the nanoscale organization and real-time analysis of T cell responses, the general principles of information gathering and processing remain incompletely understood. Here we review currently accepted key data on TCR function, discuss the limitations of current research strategies, and suggest a novel model of TCR triggering and a few promising ways of going further into the integration of available data.

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“…Another feature of T cell recognition is that it has been estimated that individual TCR may crossreact on a wide array of pMHC complexes that share structural features [46,47,33]. In addition, the influence of so-called coagonist peptides on T cell activation was shown in a recent study, which combined modeling and experiments, to depend on the affinity of the co-receptor CD8 for individual MHC class I molecules [48]. In this context a coagonist peptide is derived from endogenous proteins, is unable to stimulate T cells alone but enhances the recognition of agonist peptides [49].…”

Section: Big Questions In T Cell Immunologymentioning

confidence: 99%

Modeling the T cell immune response: a fascinating challenge

Morel

Faeder

Hawse

et al. 2014

J Pharmacokinet Pharmacodyn

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The immune system is designed to protect the organism from infection and to repair damaged tissue. An effective response requires recognition of the threat, the appropriate effector mechanism to clear the pathogen and a return to homeostasis with minimal damage to self-tissues. T cells play a central role in orchestrating the immune response at all stages of the response and have been the subject of intense study by both experimental immunologists and modelers. This review examines some of the more critical questions in T cell biology and describes the latest attempts to address those questions using approaches that combine mathematical modeling and experiments.

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Coreceptor affinity for MHC defines peptide specificity requirements for TCR interaction with coagonist peptide–MHC

Abstract: The requirement for the TCR to interact with coagonists, endogenous MHC–peptide complexes which do not themselves activate the T cell, decreases as the strength of the CD8–class I interaction increases.

Cited by 29 publications

References 56 publications

Phosphorylation of a Tyrosine Residue on Zap70 by Lck and Its Subsequent Binding via an SH2 Domain May Be a Key Gatekeeper of T Cell Receptor Signaling In Vivo

Phosphorylation of a Tyrosine Residue on Zap70 by Lck and Its Subsequent Binding via an SH2 Domain May Be a Key Gatekeeper of T Cell Receptor Signaling In Vivo

Early T Cell Activation: Integrating Biochemical, Structural, and Biophysical Cues

Modeling the T cell immune response: a fascinating challenge

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