Antagonism of HIV-specific CD4+ T cells by C-terminal truncation of a minimum epitope

Norris, Philip J.; Stone, Jon R.; Anikeeva, Nadezhda; Heitman, John W.; Wilson, Ingrid C.; Hirschkorn, Dale F.; Clark, Martin R.; Moffett, Howell F.; Cameron, Thomas O.; Sykulev, Yuri; Stern, Lawrence J.; Walker, Bruce D.

doi:10.1016/j.molimm.2005.09.004

Cited by 14 publications

(15 citation statements)

References 53 publications

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“…It is well known that HCV epitopes mutate over the course of infection to decrease MHC binding. This has been well-defined for CTL epitopes, but is less well defined for CD4+ T cell epitopes [60][61][62]. However, in the case of the HCV epitope described by Losikoff et al [42], the HCV genomic sequences appears to contain the same TCR-facing residues as highly prevalent autologous T cell epitopes, so as to acquire the potential to drive Treg responses in an HLA-diverse population.…”

Section:  Treg Epitopes In H7n9 Influenzamentioning

confidence: 99%

T cell epitope redundancy: cross-conservation of the TCR face between pathogens and self and its implications for vaccines and autoimmunity

Moise

Beseme

Tassone

et al. 2016

Expert Review of Vaccines

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SummaryT cells are extensively trained on 'self' in the thymus and then move to the periphery, where they seek out and destroy infections and regulate immune response to self-antigens. T cell receptors (TCR) on T cells' surface recognize T cell epitopes, short linear strings of amino acids presented by antigen-presenting cells. Some of these epitopes activate T effectors, while others activate regulatory T cells. It was recently discovered that T cell epitopes that are highly conserved on their TCR face with human genome sequences are often associated with T cells that regulate immune response. These TCR-cross-conserved or 'redundant epitopes' are more common in proteins found in pathogens that have co-evolved with humans than in other noncommensal pathogens. Epitope redundancy might be the link between pathogens and autoimmune disease. This article reviews recently published data and addresses epitope redundancy, the "elephant in the room" for vaccine developers and T cell immunologists.

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Section:  Treg Epitopes In H7n9 Influenzamentioning

confidence: 99%

T cell epitope redundancy: cross-conservation of the TCR face between pathogens and self and its implications for vaccines and autoimmunity

Moise

Beseme

Tassone

et al. 2016

Expert Review of Vaccines

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“…As a matter of fact, single mutations found in viral but also parasitic genomes, e.g. those in HIV [60,61] and hepatitis B and C virus [62,63,64] or plasmodium [65], and resulting in the production of such APLs were indeed described. These mutations were proposed as passive mechanisms by which microorganisms might counteract the T cellular immune response by inducing anergy in pre-existing human T cells that are specific for the original/wild-type epitopes.…”

Section: Naturally Occurring Protein Modifications Leading To Apl Formentioning

confidence: 99%

On Peptides and Altered Peptide Ligands: From Origin, Mode of Action and Design to Clinical Application (Immunotherapy)

Candia

Kratzer

Pickl

2016

Int Arch Allergy Immunol

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T lymphocytes equipped with clonotypic T cell antigen receptors (TCR) recognize immunogenic peptides only when presented in the context of their own major histocompatibility complex (MHC) molecules. Peptide loading to MHC molecules occurs in intracellular compartments (ER for class I and MIIC for class II molecules) and relies on the interaction of the respective peptides and peptide binding pockets on MHC molecules. Those peptide residues not engaged in MHC binding point towards the TCR screening for possible peptide MHC complex binding partners. Natural or intentional modification of both MHC binding registers and TCR interacting residues of peptides - leading to the formation of altered peptide ligands (APLs) - might alter the way peptides interact with TCRs and hence influence subsequent T cell activation events, and consequently T cell effector functions. This review article summarizes how APLs were detected and first described, current concepts of how APLs modify T cellular signaling, which biological mechanisms might force the generation of APLs in vivo, and how peptides and APLs might be used for the benefit of patients suffering from allergic or autoimmune diseases.

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“…As a result, it has been impossible to make kinetic or thermodynamic measurements to better appreciate how a TCR distinguishes its cognate ligand from a subtly different APL to give distinct functional effects. Approaches using pMHC or TCR tetramers have provided estimates of K D values for low affinity interactions (Deng et al, 2007; Huseby et al, 2006; Norris et al, 2006), but such methods cannot be used to obtain binding kinetic parameters. We have therefore employed M15, a high-affinity single-chain TCR (scTCR) engineered by in vitro evolution of 3.L2 to probe these important interactions with APLs.…”

Section: ) Introductionmentioning

confidence: 99%

High-affinity T cell receptor differentiates cognate peptide–MHC and altered peptide ligands with distinct kinetics and thermodynamics

Persaud

Donermeyer

Weber

et al. 2010

Molecular Immunology

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Interactions between the T cell receptor and cognate peptide-MHC are crucial initiating events in the adaptive immune response. These binding events are highly specific yet occur with micromolar affinity. Even weaker interactions between TCR and self-pMHC complexes play critical regulatory roles in T cell development, maintenance and coagonist activity. Due to their low affinity, the kinetics and thermodynamics of such weak interactions are difficult to study. In this work, we used M15, a high-affinity TCR engineered from the 3.L2 TCR system, to study the binding properties, thermodynamics, and specificity of two altered peptide ligands (APLs). Our affinity measurements of the high-affinity TCR support the view that the wild type TCR binds these APLs in the millimolar affinity range, and hence very low affinities can still elicit biological functions. Finally, single methylene differences among the APLs gave rise to strikingly different binding thermodynamics. These minor changes in the pMHC antigen were associated with significant and unpredictable changes in both the entropy and enthalpy of the reaction. As the identical TCR was analyzed with several structurally similar ligands, the distinct thermodynamic binding profiles provide a mechanistic perspective on how exquisite antigen specificity is achieved by the T cell receptor.

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Antagonism of HIV-specific CD4+ T cells by C-terminal truncation of a minimum epitope

Cited by 14 publications

References 53 publications

T cell epitope redundancy: cross-conservation of the TCR face between pathogens and self and its implications for vaccines and autoimmunity

T cell epitope redundancy: cross-conservation of the TCR face between pathogens and self and its implications for vaccines and autoimmunity

On Peptides and Altered Peptide Ligands: From Origin, Mode of Action and Design to Clinical Application (Immunotherapy)

High-affinity T cell receptor differentiates cognate peptide–MHC and altered peptide ligands with distinct kinetics and thermodynamics

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