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

2021 ◽  
Vol 118 (29) ◽  
pp. e2019639118
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 ◽  
Peptide Antigens ◽  
Controlled Systems ◽  
Histocompatibility Complex ◽  
The Relationship

CD8+ 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 two intrinsically controlled systems 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.

scholarly journals Recognition of multiple peptide cores by a single T cell receptor.

1995 ◽  
Vol 182 (2) ◽  
pp. 531-539 ◽  
Author(s):  
N K Nanda ◽  
K K Arzoo ◽  
H M Geysen ◽  
A Sette ◽  
E E Sercarz
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Clone ◽  
Cell Receptor ◽  
Peptide Ligands ◽  
Present Evidence ◽  
Mhc Molecules ◽  
Histocompatibility Complex ◽  
T Cell Clone ◽  
Contact Residues

We present evidence that a single T cell clone can recognize at least five different overlapping peptides, each with its distinct core structure, in the context of the same major histocompatibility complex (MHC) molecule. Distinct core residues are crucial for triggering the T cell receptor (TCR) in each case. These results suggest that the TCR (a) has multiple sets of contact residues for alternative peptide-MHC ligands, the binding to any one of which can trigger the cell; and/or (b) is able to attach to the peptide-MHC complex in more than one orientation. In this sense, the TCR is a multisubsite structure capable of being stimulated by a variety of peptide ligands associated with the same MHC molecules.

scholarly journals Enhancing and inhibitory motifs have coevolved to regulate CD4 activity

2021 ◽  
Author(s):  
Mark S. Lee ◽  
Peter J. Tuohy ◽  
Caleb Kim ◽  
Katrina Lichauco ◽  
Heather L. Parrish ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Purifying Selection ◽  
Cell Receptor ◽  
Specific Information ◽  
Transmembrane Receptors ◽  
Peptide Antigens ◽  
And Function ◽  
Intracellular Domains

SUMMARYCD4+ T cells use T cell receptor (TCR)-CD3 complexes, and CD4, to respond to peptide antigens within MHCII molecules (pMHCII). We report here that, through ∼435 million years of evolution in jawed vertebrates, purifying selection has shaped motifs in the extracellular, transmembrane, and intracellular domains of eutherian CD4 that both enhance pMHCII responses and are coevolving with residues in an intracellular motif that inhibits pMHCII responses. Importantly, while CD4 interactions with the Src kinase, Lck, are classically viewed as the key determinant of CD4’s contribution to pMHCII responses, we found that without the inhibitory motif CD4-Lck interactions are not necessary for robust responses to pMHCII. In summary, motifs that mediate events on the outside and inside of CD4+ T cells coevolved to finetune the relay of pMHCII-specific information across the membrane. These results have implications for the evolution and function of complex transmembrane receptors and for biomimetic engineering.

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