Human T-cell clones recognize chemically synthesized peptides of influenza haemagglutinin

Lamb, Jonathan R.; Eckels, David D.; Lake, Phil; Woody, James N.; Green, Nicola

doi:10.1038/300066a0

Cited by 212 publications

(124 citation statements)

References 16 publications

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“…This monomer antagonism of T cell activation is also seen in the human CD4 ϩ T cell clone HA1.7, which is specific to the human class II MHC protein HLA-DR1 in complex with the HA peptide (30). The TCR down-regulation induced by treating the HA1.7 T cells with a DR1-HA dimer is reduced when DR1-HA is added to the cells in the form of a monomer (38) (Fig.…”

Section: Monomeric Mhc-peptide Binding Antagonizes Activation Responsmentioning

confidence: 93%

CD8 T Cells, Like CD4 T Cells, Are Triggered by Multivalent Engagement of TCRs by MHC-Peptide Ligands but Not by Monovalent Engagement

Stone

Stern

2006

The Journal of Immunology

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T cell activation is initiated by recognition of antigenic peptide presented in complex with MHC molecules on the surface of APCs. The mechanism by which this recognition occurs is still unclear, and many models exist in the literature. CD4 T cells have been shown to respond to soluble oligomers of activating class II MHC-peptide complexes, but not to soluble monomers. In determining the reactivity of CD8 T cells to soluble activating class I MHC-peptide complexes, a complicating phenomenon had been observed whereby peptide from soluble complexes was loaded onto cell surface MHCs on the T cells and re-presented to other T cells, clouding the true valency requirement for activation. This study uses soluble allogeneic class I MHC-peptide monomers and oligomers to stimulate murine CD8 T cells without the possible complication of peptide re-presentation. The results show that MHC class I monomers bind to, but do not activate, CD8 T cells whether the cells are in solution or adhered to a surface. Monomeric MHC class I binding can antagonize the stimulation triggered by soluble oligomers, a phenomenon also observed for CD4 T cells. Dimeric engagement is necessary and sufficient to stimulate downstream activation processes including TCR down-regulation, Zap70 phosphorylation, and CD25 and CD69 up-regulation, even in T cells that do not express the MHC coreceptor CD8. Thus, the valency dependence of the response of CD8 T cells to soluble MHC-peptide reagents is the same as previously observed for CD4 T cells.

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Section: Monomeric Mhc-peptide Binding Antagonizes Activation Responsmentioning

confidence: 93%

CD8 T Cells, Like CD4 T Cells, Are Triggered by Multivalent Engagement of TCRs by MHC-Peptide Ligands but Not by Monovalent Engagement

Stone

Stern

2006

The Journal of Immunology

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“…Antigen presentation by M and DCs was determined by measuring proliferation and IFN-␥ secretion of the HLA-DR2-restricted CD4 ϩ T cell clone R2F10 that is specific for the 60-kDa heat-shock protein (amino acids 418-427) of Mycobacterium leprae (21) or the HLA-DR1-restricted CD4 ϩ T cell clone HA1.7 that is specific for the hemagglutinin (amino acids 306-318) of influenza virus (22). Briefly, antigen-presenting cells were harvested and seeded in triplicates at 2.…”

Section: Methodsmentioning

confidence: 99%

Human IL-23-producing type 1 macrophages promote but IL-10-producing type 2 macrophages subvert immunity to (myco)bacteria

Verreck

Boer

Langenberg

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

834

748

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“…Peptide variants of CLIP (Ac-VSRMRMATP-LδMQ, where δ is 2,4-diaminobutyric acid), derived from the class II-associated invariant chain (17), HA (Ac-PRFV-KQNTLRLAT), derived from influenza virus hemagglutinin (14), and MA (Ac-SGPLKAEIAQRLE), derived from influenza virus matrix protein (39)(40)(41), were synthesized by solid-phase FMOC chemistry, deprotected, purified by reverse-phase HLPC, and analyzed by matrix-assisted laser desorption mass spectrometry and quantitative amino acid analysis to confirm the absence of incomplete synthetic or deprotection products. Underscored side chains indicate positions of unique amino groups used for introduction of fluorescent labels.…”

Section: Methodsmentioning

confidence: 99%

A Three-Step Kinetic Mechanism for Peptide Binding to MHC Class II Proteins

2000

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Peptide binding reactions of class II MHC proteins exhibit unusual kinetics, with extremely slow apparent rate constants for the overall association (<100 M -1 s -1 ) and dissociation (<10 -5 s -1 ) processes. Various linear and branched pathways have been proposed to account for these data. Using fluorescence resonance energy transfer between tryptophan residues in the MHC peptide binding site and aminocoumarin-labeled peptides, we measured real-time kinetics of peptide binding to empty class II MHC proteins. Our experiments identified an obligate intermediate in the binding reaction. The observed kinetics were consistent with a binding mechanism that involves an initial bimolecular binding step followed by a slow unimolecular conformational change. The same mechanism is observed for different peptide antigens. In addition, we noted a reversible inactivation of the empty MHC protein that competes with productive binding. The implications of this kinetic mechanism for intracellular antigen presentation pathways are discussed.Proteins encoded by the major histocompatibility complex (MHC) 1 gene locus bind peptide antigens and display them at the cell surface for inspection by the immune system as part of the mechanism by which foreign material in the body is recognized and removed (1). Class II MHC proteins generally are found on specialized immune system cells such as B cells, macrophages, and dendritic cells, but they can be expressed by most cell types in response to inflammation or infection (2). Newly synthesized class II MHC R-and -glycoprotein subunits associate with a chaperonin-like invariant chain protein, which places an extended loop in the class II peptide binding site and directs transport to an endosomal compartment (3). Endosomal proteins cleave the invariant chain, and the bound fragment is exchanged for peptides generated from cell-surface and endocytosed proteins, in a poorly characterized process catalyzed by the peptide-exchange factor HLA-DM (4). MHC-peptide complexes then are transported to the cell surface for inspection by T-cell receptors on CD4 + T lymphocytes. Crystal structures have been determined for several human and murine class II MHC proteins in complex with defined peptides (5-13). In each case, the peptide was bound in a polyproline type II-like conformation, with several side chains projecting into specificity-determining pockets within the overall peptide binding groove, and with many additional contacts between the MHC proteins and the main chain of the bound peptide.Initially, in vitro kinetic measurements of peptide binding to purified class II MHC proteins were interpreted in terms of the simple bimolecular reaction shown in Scheme 1 (14): Physical and chemical characterization of purified class II MHC revealed that they carried complex mixtures of tightly bound endogenous peptides (15-19). The stoichiometry of binding for peptide added to these preparations was quite low. Many of the natural peptide ligands had extremely long half-lives, often on the order of ...

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Human T-cell clones recognize chemically synthesized peptides of influenza haemagglutinin

Cited by 212 publications

References 16 publications

CD8 T Cells, Like CD4 T Cells, Are Triggered by Multivalent Engagement of TCRs by MHC-Peptide Ligands but Not by Monovalent Engagement

CD8 T Cells, Like CD4 T Cells, Are Triggered by Multivalent Engagement of TCRs by MHC-Peptide Ligands but Not by Monovalent Engagement

Human IL-23-producing type 1 macrophages promote but IL-10-producing type 2 macrophages subvert immunity to (myco)bacteria

A Three-Step Kinetic Mechanism for Peptide Binding to MHC Class II Proteins

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