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

2010 ◽  
Vol 47 (9) ◽  
pp. 1793-1801 ◽  
Author(s):  
Stephen P. Persaud ◽  
David L. Donermeyer ◽  
K. Scott Weber ◽  
David M. Kranz ◽  
Paul M. Allen
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Peptide Ligands ◽  
Altered Peptide Ligands ◽  
Kinetics And Thermodynamics ◽  
High Affinity

scholarly journals Structural basis for T cell recognition of altered peptide ligands: a single T cell receptor can productively recognize a large continuum of related ligands.

1996 ◽  
Vol 184 (4) ◽  
pp. 1259-1268 ◽  
Author(s):  
G J Kersh ◽  
P M Allen
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Clone ◽  
Cell Receptor ◽  
Peptide Ligands ◽  
Structural Basis ◽  
Side Chain ◽  
Contact Residue ◽  
Altered Peptide Ligands ◽  
T Cell Clone

T cells recognize short linear peptides bound to major histocompatibility complex (MHC)-encoded molecules. Subtle molecular changes in peptide antigens produce altered peptide ligands (APLs), which induce different T cell responses from those induced by the antigenic ligand. A molecular basis for how these slight molecular variations lead to such different consequences for the T cell has not been described. To address this issue, we have made amino acid substitutions at the primary T cell receptor (TCR) contact residue of the murine hemoglobin determinant, Hb(64-76)/I-Ek and produced 12 peptides that interact with the TCR of the T cell clone 3.L2. The 3.L2 T cell responds to these peptides, which vary 1 million-fold in their activity, and enables them to be ranked according to their relative ability to signal through the 3.L2 TCR. Such a ranking reveals that the ability of the 3.L2 T cell to respond to these peptides depends on how well the structure of the side chain at the primary TCR contact site mimics that of the Asn residue present in the antigenic ligand. The reactivity of the 3.L2 T cell also depends on an MHC contact residue that is next to the primary TCR contact residue, suggesting that conformation of the Asn side chain is also important. By using nonnatural amino acids at a TCR contact residue, we have demonstrated that APLs can be rationally designed based on structure. These data are consistent with a model in which the affinity of a peptide-MHC complex for the TCR determines how the T cell will respond.

scholarly journals Altered Peptide Ligands Induce Delayed CD8-T Cell Receptor Interaction—a Role for CD8 in Distinguishing Antigen Quality

Immunity ◽  
2006 ◽  
Vol 25 (2) ◽  
pp. 203-211 ◽  
Author(s):  
Pia P. Yachi ◽  
Jeanette Ampudia ◽  
Tomasz Zal ◽  
Nicholas R.J. Gascoigne
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cd8 T Cell ◽  
Cell Receptor ◽  
Peptide Ligands ◽  
Receptor Interaction ◽  
Altered Peptide Ligands

scholarly journals Altered Peptide Ligands Impact the Diversity of Polyfunctional Phenotypes in T Cell Receptor Gene-Modified T Cells

2018 ◽  
Vol 26 (4) ◽  
pp. 996-1007 ◽  
Author(s):  
Timothy T. Spear ◽  
Yuan Wang ◽  
Thomas W. Smith ◽  
Patricia E. Simms ◽  
Elizabeth Garrett-Mayer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Receptor Gene ◽  
Cell Receptor ◽  
Peptide Ligands ◽  
Altered Peptide Ligands ◽  
T Cell Receptor Gene ◽  
Cell Receptor Gene

scholarly journals Cd4+ T Cells from Lupus-Prone Mice Are Hyperresponsive to T Cell Receptor Engagement with Low and High Affinity Peptide Antigens

2001 ◽  
Vol 193 (3) ◽  
pp. 329-338 ◽  
Author(s):  
George S. Vratsanos ◽  
Sungsoo Jung ◽  
Yeong-Min Park ◽  
Joe Craft
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Peptide Ligands ◽  
Altered Peptide Ligands ◽  
Lower Affinity

Polyclonal CD4+ T cell activation is characteristic of spontaneous lupus. As a potential explanation for this phenotype, we hypothesized that T cells from lupus-prone mice are intrinsically hyperresponsive to stimulation with antigen, particularly to those peptide ligands having a low affinity for the T cell receptor (TCR). To test this hypothesis, we backcrossed the α and β chain genes of the AND TCR specific for amino acids 88–104 of pigeon cytochrome C (PCC) to the Fas-intact MRL/Mp+Fas-lpr and to the H-2k–matched control backgrounds B10.BR and CBA/CaJ (MRL.AND, B10.AND, and CBA.AND, respectively), and assessed naive CD4+ TCR transgenic T cell activation in vitro after its encounter with cognate antigen and lower affinity altered peptide ligands (APLs). MRL.AND T cells, compared with control B10.AND and CBA.AND cells, proliferated more when stimulated with agonist antigen. More strikingly, MRL.AND T cells proliferated significantly more and produced more interleukin 2 when stimulated with the APLs of PCC 88–104, having lower affinity for the transgenic TCR. These results imply that one of the forces driving polyclonal activation of α/β T cells in lupus is an intrinsically heightened response to peptide antigen, particularly those with low affinity for the TCR, independent of the nature of the antigen-presenting cell and degree of costimulation.

scholarly journals CD8 coreceptor-mediated focusing can reorder the agonist hierarchy of peptide ligands recognized via the T cell receptor

2020 ◽  
Author(s):  
Mathew Clement ◽  
Lea Knezevic ◽  
Tamsin Dockree ◽  
James E. McLaren ◽  
Kristin Ladell ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Theoretical Models ◽  
Cell Receptor ◽  
Dissociation Rate ◽  
Peptide Ligands ◽  
Controlled System ◽  
Peptide Antigens ◽  
Histocompatibility Complex ◽  
The Relationship

ABSTRACTCD8+ T cells are inherently cross-reactive and recognize numerous peptide antigens in the context of a given major histocompatibility complex class I (MHCI) molecule via the clonotypically expressed T cell receptor (TCR). The lineally expressed coreceptor CD8 interacts coordinately with MHCI at a distinct and largely invariant site to slow the TCR/peptide-MHCI (pMHCI) dissociation rate and enhance antigen sensitivity. However, this biological effect is not necessarily uniform, and theoretical models suggest that antigen sensitivity can be modulated in a differential manner by CD8. We used an intrinsically controlled system to determine how the relationship between the TCR/pMHCI interaction and the pMHCI/CD8 interaction affects the functional sensitivity of antigen recognition. Our data show that modulation of the pMHCI/CD8 interaction can reorder the agonist hierarchy of peptide ligands across a spectrum of affinities for the TCR.SIGNIFICANCESufficient immune coverage of the peptide universe within a finite host requires highly degenerate T cell receptors (TCRs). However, this inherent need for antigen cross-recognition is associated with a high risk of autoimmunity, which can only be mitigated by a process of adaptable specificity. We describe a mechanism that resolves this conundrum by allowing individual clonotypes to focus on specific peptide ligands without alterations to the structure of the TCR.

scholarly journals A Kinetic Threshold between Negative and Positive Selection Based on the Longevity of the T Cell Receptor–Ligand Complex

1999 ◽  
Vol 189 (10) ◽  
pp. 1531-1544 ◽  
Author(s):  
Calvin B. Williams ◽  
Deborah L. Engle ◽  
Gilbert J. Kersh ◽  
J. Michael White ◽  
Paul M. Allen
Keyword(s):  
T Cells ◽  
T Cell ◽  
Positive Selection ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Ligand Complex ◽  
Altered Peptide Ligands ◽  
Self Peptides ◽  
Selection Of

We have developed a unique in vivo system to determine the relationship between endogenous altered peptide ligands and the development of major histocompatibility complex class II– restricted T cells. Our studies use the 3.L2 T cell receptor (TCR) transgenic mouse, in which T cells are specific for Hb(64–76)/I-Ek and positively selected on I-Ek plus self-peptides. To this endogenous peptide repertoire, we have individually added one of six well-characterized 3.L2 ligands. This transgenic approach expands rather than constrains the repertoire of self-peptides. We find that a broad range of ligands produce negative selection of thymocytes in vivo. When compared with the in vitro TCR–ligand binding kinetics, we find that these negatively selecting ligands all have a half-life of 2 s or greater. Additionally, one of two ligands examined with no detectable binding to the 3.L2 TCR and no activity on mature 3.L2 T cells (Q72) enhances the positive selection of transgenic thymocytes in vivo. Together, these data establish a kinetic threshold between negative and positive selection based on the longevity of TCR–ligand complexes.

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