Crystal Structures of Two H-2Db/Glycopeptide Complexes Suggest a Molecular Basis for CTL Cross-Reactivity

Glithero, Ann; Tormo, J.; Haurum, John S.; Arsequell, Gemma; Valencia, Gregorio; Edwards, Jeff; Springer, Sebastian; Townsend, Alain; Pao, Ya-Lan; Wormald, Mark R.; Dwek, Raymond A.; Jones, E Y; Elliott, Tim

doi:10.1016/s1074-7613(00)80007-2

Cited by 121 publications

(105 citation statements)

References 45 publications

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“…Digesting MP with proteinase K, a nonspecific protease, dramatically diminished P1D6 stimulation, indicating a requirement for the protein core. However, the possibility that the protein was required to maintain proper carbohydrate conformation while being presented cannot be entirely ruled out, especially as crystallographic evidence supports the ability of MHC to accommodate monosaccharides (55). A requirement for an MHC class II-restricted pathway was suggested by our data demonstrating splenocytes from Ii Ϫ/Ϫ fail to stimulate the MP-dependent CD4 ϩ T cell hybridoma cell line.…”

Section: Discussionmentioning

confidence: 81%

Optimal T Cell Responses to Cryptococcus neoformans Mannoprotein Are Dependent on Recognition of Conjugated Carbohydrates by Mannose Receptors

Mansour

Schlesinger

Levitz

2002

The Journal of Immunology

139

119

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Cryptococcosis is a leading cause of death among individuals with compromised T cell function. Soluble Cryptococcus neoformans mannoproteins (MP) have emerged as promising vaccine candidates due to their capacity to elicit delayed-type hypersensitivity and Th type 1-like cytokines, both critical to the clearance of this pathogenic yeast. In this study, the mechanisms responsible for the potent immunostimulatory properties of MP were explored. Using Chinese hamster ovary cells expressing human macrophage mannose receptor (MMR), we determined that MP is a MMR ligand. Functionally, competitive blockade of multilectin mannose receptors (MR) on APCs diminished MP-dependent stimulation of primary T cells from immunized mice and the MP-reactive CD4+ T cell hybridoma, P1D6, by 72 and 99%, respectively. Removal of O-linked saccharides from MP by β-elimination inhibited MP-dependent stimulation of P1D6 and primary T cells by 89 and 90%, respectively. In addition, MP-dependent stimulation of P1D6 was abrogated after digestion with proteinase K, suggesting the protein core of MP contributed the antigenic moiety presented by APC. Stimulation of P1D6 by MP also was abolished using APC obtained from invariant chain-deficient mice, demonstrating Ag presentation was MHC class II restricted. Our data suggest that MP is a ligand for the MMR and that T cell stimulation is functionally inhibited either by competitive blockade of MR or by removal of carbohydrate residues critical for recognition. The demonstration that efficient T cell responses to MP require recognition of terminal mannose groups by MMR provides both a molecular basis for the immunogenicity of cryptococcal MP and support for vaccination strategies that target MR.

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Section: Discussionmentioning

confidence: 81%

Optimal T Cell Responses to Cryptococcus neoformans Mannoprotein Are Dependent on Recognition of Conjugated Carbohydrates by Mannose Receptors

Mansour

Schlesinger

Levitz

2002

The Journal of Immunology

139

119

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“…The crystal structure of this binary complex reveals a highly solvent-exposed, centrally bulged peptide that displays sufficient mobility to adopt two different conformations within the antigen-binding cleft. Solvent-exposed saccharide residues in glycopeptides presented by MHC molecules have also been observed to protrude substantially from the peptide-binding groove (32). Recently, unusually long MHC-IIrestricted epitopes have been shown to adopt a ␤-hairpin structure at the C-terminal end of the peptide-binding groove (33); however, this has not been observed for longer class I peptides.…”

mentioning

confidence: 99%

High Resolution Structures of Highly Bulged Viral Epitopes Bound to Major Histocompatibility Complex Class I

Tynan

Borg

Miles

et al. 2005

Journal of Biological Chemistry

151

163

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“…The pathogenic importance of the latter recognition has led us to investigate the structural basis of this cross-reactivity. While many structural studies of multiple peptide recognition on a single self-MHC molecule exist (10,11), precedents for dual MHC recognition by one TCR involve alloreactivity (12) or xenoreactivity (13).…”

mentioning

confidence: 99%

Molecular Basis for Recognition of an Arthritic Peptide and a Foreign Epitope on Distinct MHC Molecules by a Single TCR

Basu

Horváth

Matsumoto

et al. 2000

The Journal of Immunology

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KRN TCR transgenic T cells recognize two self-MHC molecules: a foreign peptide, bovine RNase 42–56, on I-Ak and an autoantigen, glucose-6-phosphate isomerase 282–294, on I-Ag7. Because the latter recognition event initiates a disease closely resembling human rheumatoid arthritis, we investigated the structural basis of this pathogenic TCR’s dual specificity. While peptide recognition is altered to a minor degree between the MHC molecules, we show that the receptor’s cross-reactivity critically depends upon a TCR contact residue completely conserved in the foreign and self peptides. Further, the altered recognition of peptide derives from discrete differences on the MHC recognition surfaces and not the disparate binding grooves. This work provides a detailed structural comparison of an autoreactive TCR’s interactions with naturally occurring peptides on distinct MHC molecules. The capacity to interact with multiple self-MHCs in this manner increases the number of potentially pathogenic self-interactions available to a T cell.

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Crystal Structures of Two H-2Db/Glycopeptide Complexes Suggest a Molecular Basis for CTL Cross-Reactivity

Cited by 121 publications

References 45 publications

Optimal T Cell Responses to Cryptococcus neoformans Mannoprotein Are Dependent on Recognition of Conjugated Carbohydrates by Mannose Receptors

Optimal T Cell Responses to Cryptococcus neoformans Mannoprotein Are Dependent on Recognition of Conjugated Carbohydrates by Mannose Receptors

High Resolution Structures of Highly Bulged Viral Epitopes Bound to Major Histocompatibility Complex Class I

Molecular Basis for Recognition of an Arthritic Peptide and a Foreign Epitope on Distinct MHC Molecules by a Single TCR

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