scholarly journals Structural Basis of Cytochrome c Presentation by IEk

2002 ◽  
Vol 195 (8) ◽  
pp. 1043-1052 ◽  
Author(s):  
Daved H. Fremont ◽  
Shaodong Dai ◽  
Herbert Chiang ◽  
Frances Crawford ◽  
Philippa Marrack ◽  
...  
Keyword(s):  
T Cell ◽  
Cytochrome C ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Structural Basis ◽  
Anchor Residue ◽  
T Cell Antigens ◽  
Binding Groove ◽  
The Many ◽  
The Cost

The COOH-terminal peptides of pigeon and moth cytochrome c, bound to mouse IEk, are two of the most thoroughly studied T cell antigens. We have solved the crystal structures of the moth peptide and a weak agonist–antagonist variant of the pigeon peptide bound to IEk. The moth peptide and all other peptides whose structures have been solved bound to IEk, have a lysine filling the p9 pocket of IEk. However, the pigeon peptide has an alanine at p9 shifting the lysine to p10. Rather than kinking to place the lysine in the anchor pocket, the pigeon peptide takes the extended course through the binding groove, which is characteristic of all other peptides bound to major histocompatibility complex (MHC) class II. Thus, unlike MHC class I, in which peptides often kink to place optimally anchoring side chains, MHC class II imposes an extended peptide conformation even at the cost of a highly conserved anchor residue. The substitution of Ser for Thr at p8 in the variant pigeon peptide induces no detectable surface change other than the loss of the side chain methyl group, despite the dramatic change in recognition by T cells. Finally, these structures can be used to interpret the many published mutational studies of these ligands and the T cell receptors that recognize them.

Structural basis for the recognition of mutant self by a tumor-specific, MHC class II–restricted T cell receptor

2007 ◽  
Vol 8 (4) ◽  
pp. 398-408 ◽  
Author(s):  
Lu Deng ◽  
Ries J Langley ◽  
Patrick H Brown ◽  
Gang Xu ◽  
Leslie Teng ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Mhc Class Ii ◽  
Cell Receptor ◽  
Class Ii ◽  
Structural Basis

scholarly journals Structure of a Complex of the Human α/β T Cell Receptor (TCR) HA1.7, Influenza Hemagglutinin Peptide, and Major Histocompatibility Complex Class II Molecule, HLA-DR4 (DRA*0101 and DRB1*0401)

2002 ◽  
Vol 195 (5) ◽  
pp. 571-581 ◽  
Author(s):  
Jens Hennecke ◽  
Don C. Wiley
Keyword(s):  
Major Histocompatibility Complex ◽  
T Cell ◽  
T Cell Receptor ◽  
Mhc Class Ii ◽  
Peptide Binding ◽  
Cell Receptor ◽  
Class Ii ◽  
Histocompatibility Complex ◽  
Peptide Binding Groove ◽  
Binding Groove

The α/β T cell receptor (TCR) HA1.7 specific for the hemagglutinin (HA) antigen peptide from influenza A virus is HLA-DR1 restricted but cross-reactive for the HA peptide presented by the allo-major histocompatibility complex (MHC) class II molecule HLA-DR4. We report here the structure of the HA1.7/DR4/HA complex, determined by X-ray crystallography at a resolution of 2.4 Å. The overall structure of this complex is very similar to the previously reported structure of the HA1.7/DR1/HA complex. Amino acid sequence differences between DR1 and DR4, which are located deep in the peptide binding groove and out of reach for direct contact by the TCR, are able to indirectly influence the antigenicity of the pMHC surface by changing the conformation of HA peptide residues at position P5 and P6. Although TCR HA1.7 is cross-reactive for HA presented by DR1 and DR4 and tolerates these conformational differences, other HA-specific TCRs are sensitive to these changes. We also find a dependence of the width of the MHC class II peptide-binding groove on the sequence of the bound peptide by comparing the HA1.7/DR4/HA complex with the structure of DR4 presenting a collagen peptide. This structural study of TCR cross-reactivity emphasizes how MHC sequence differences can affect TCR binding indirectly by moving peptide atoms.

scholarly journals Structural Basis for the Restoration of TCR Recognition of an MHC Allelic Variant by Peptide Secondary Anchor Substitution

2004 ◽  
Vol 200 (11) ◽  
pp. 1445-1454 ◽  
Author(s):  
Michael J. Miley ◽  
Ilhem Messaoudi ◽  
Beatrix M. Metzner ◽  
Yudong Wu ◽  
Janko Nikolich-Žugich ◽  
...  
Keyword(s):  
T Cell ◽  
Mhc Class I ◽  
Peptide Binding ◽  
Cell Receptor ◽  
Class I ◽  
Structural Basis ◽  
Anchor Residue ◽  
Peptide Binding Groove ◽  
Binding Groove ◽  
Simplex Virus

Major histocompatibility complex (MHC) class I variants H-2Kb and H-2Kbm8 differ primarily in the B pocket of the peptide-binding groove, which serves to sequester the P2 secondary anchor residue. This polymorphism determines resistance to lethal herpes simplex virus (HSV-1) infection by modulating T cell responses to the immunodominant glycoprotein B498-505 epitope, HSV8. We studied the molecular basis of these effects and confirmed that T cell receptors raised against Kb–HSV8 cannot recognize H-2Kbm8–HSV8. However, substitution of SerP2 to GluP2 (peptide H2E) reversed T cell receptor (TCR) recognition; H-2Kbm8–H2E was recognized whereas H-2Kb–H2E was not. Insight into the structural basis of this discrimination was obtained by determining the crystal structures of all four MHC class I molecules in complex with bound peptide (pMHCs). Surprisingly, we find no concerted pMHC surface differences that can explain the differential TCR recognition. However, a correlation is apparent between the recognition data and the underlying peptide-binding groove chemistry of the B pocket, revealing that secondary anchor residues can profoundly affect TCR engagement through mechanisms distinct from the alteration of the resting state conformation of the pMHC surface.

Biased T-cell receptor usage is associated with allelic variation in the MHC class II peptide binding groove

1999 ◽  
Vol 49 (6) ◽  
pp. 532-540 ◽  
Author(s):  
B. Yassine-Diab ◽  
P. Carmichael ◽  
Fatima-Ezzahra L'Faqihi ◽  
Giovanna Lombardi ◽  
Sarah Deacock ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Mhc Class Ii ◽  
Allelic Variation ◽  
Peptide Binding ◽  
Cell Receptor ◽  
Class Ii ◽  
Receptor Usage ◽  
Peptide Binding Groove ◽  
Binding Groove

scholarly journals Long-term surviving cancer patients as a source of therapeutic TCR

2020 ◽  
Vol 69 (5) ◽  
pp. 859-865 ◽  
Author(s):  
Else Marit Inderberg ◽  
Sébastien Wälchli
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Mhc Class Ii ◽  
Therapeutic Potential ◽  
Cancer Control ◽  
Class Ii ◽  
The Cost

AbstractWe have established a platform for the isolation of tumour-specific TCR from T cells of patients who experienced clinical benefit from cancer vaccination. In this review we will present the rationale behind this strategy and discuss the advantages of working with “natural” wild type TCRs. Indeed, the general trend in the field has been to use various modifications to enhance the affinity of such therapeutic TCRs. This was done to obtain stronger T cell responses, often at the cost of safety. We further describe antigen targets and recent in vitro and in vivo results obtained to validate them. We finally discuss the use of MHC class II-restricted TCR in immunotherapy. Typically cellular anti-tumour immune responses have been attributed to CD8 T cells; however, we isolated mainly CD4 T cells. Importantly, these MHC class II-restricted TCRs have the potential to induce broad, long lasting immune responses that enable cancer control. The use of CD4 T cell-derived TCRs for adoptive immunotherapy has so far been limited and we will here discuss their therapeutic potential.

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