Topology of T cell receptor-peptide/class I MHC interaction defined by charge reversal complementation and functional analysis

Chang, Huiyou; Smolyar, Alex; Spoerl, R.; Witte, Torsten; Yao, Y.; Goyarts, E.; Nathenson, Stanley G.; Reinherz, Ellis L.

doi:10.1006/jmbi.1997.1169

Cited by 39 publications

(33 citation statements)

References 76 publications

(86 reference statements)

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“…The site-directed mutagenesis of the N30.7 CDR3␤ leading to the S96A, S96T, G97A, and E101A TCR mutants was done by cassette mutagenesis as described by Goyarts et al (30). The T cell hybridoma expressing the N15 TCR was kindly provided Dr. H.-C. Chang (31).…”

Section: Activation Of T Hybridomas By Vsv Peptidementioning

confidence: 99%

Altered Peptide Ligand-Mediated TCR Antagonism Can Be Modulated by a Change in a Single Amino Acid Residue Within the CDR3β of an MHC Class I-Restricted TCR

Kalergis

Nathenson

2000

The Journal of Immunology

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The Ag receptor of cytotoxic CD8+ T lymphocytes recognizes peptides of 8–10 aa bound to MHC class I molecules. This Ag recognition event leads to the activation of the CD8+ lymphocyte and subsequent lysis of the target cell. Altered peptide ligands are analogues derived from the original antigenic peptide that commonly carry amino acid substitutions at TCR contact residues. TCR engagement by these altered peptide ligands usually impairs normal T cell function. Some of these altered peptide ligands (antagonists) are able to specifically antagonize and inhibit T cell activation induced by the wild-type antigenic peptide. Despite significant advances made in understanding TCR antagonism, the molecular interactions between the TCR and the MHC/peptide complex responsible for the inhibitory activity of antagonist peptides remain elusive. To approach this question, we have identified altered peptide ligands derived from the vesicular stomatitis virus peptide (RGYVYQGL) that specifically antagonize an H-2Kb/vesicular stomatitis virus-specific TCR. Furthermore, by site-directed mutagenesis, we altered single amino acid residues of the complementarity-determining region 3 of the β-chain of this TCR and tested the effect of these point mutations on Ag recognition and TCR antagonism. Here we show that a single amino acid change on the TCR CDR3β loop can modulate the TCR-antagonistic properties of an altered peptide ligand. Our results highlight the role of the TCR complementarity-determining region 3 loops for controlling the nature of the T cell response to TCR/altered peptide ligand interactions, including those leading to TCR antagonism.

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Section: Activation Of T Hybridomas By Vsv Peptidementioning

confidence: 99%

Altered Peptide Ligand-Mediated TCR Antagonism Can Be Modulated by a Change in a Single Amino Acid Residue Within the CDR3β of an MHC Class I-Restricted TCR

Kalergis

Nathenson

2000

The Journal of Immunology

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“…A complete censorship for R at this position (Rp1) is explained by its charge and size that would affect viral morphogenesis [26]. Unfortunately, mutational analysis previously indicated that the Rp1 residue is critical for recognition of N15 [27]. It was previously shown that p4 and p6 residues also interact with N15 [23] and that p4 V 1 I mutants remain agonist for N15.…”

Section: Discussionmentioning

confidence: 99%

Phage‐displayed libraries of peptide/major histocompatibility complexes

et al. 2004

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Characterizing peptide epitopes targeted by major histocompatibility complex (MHC)-restricted T cells of unknown specificity would have broad implications. In this article we introduce and validate an original phage-displayed library of noncovalent complexes of peptide and MHC (P/MHC). We show that soluble MHC molecules associate with peptides presented by a phage, thereby resulting in the formation of multivalent P/MHC phages. Complex formation is stabilized by the interaction of the soluble partner (MHC) with two components, peptide and g 2-microglobulin, both of which are covalently linked to the phage. As proof of concept, we have used this strategy to express peptide libraries in the context of H-2K b . Using monoclonal antibody 25D (specific for ovalbumin/H-2K b ) as a template to screen the library, we were able to select a variant epitope functionally and structurally related to the wild-type peptide. Interaction studies between monoclonal antibody 25D and cells suggest that the variant peptide has been selected on the basis of a decreased dissociation rate between the peptide/H-2K b complex and its ligand. A weak agonist of the N15 TCR (vesicular stomatitis virus/H-2K b -specific) was also isolated from another P/MHC library. This strategy opens up new perspectives for antigen discovery and the manipulation of T cell responses.

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“…␤ Occupies Site 1-We recently showed that CD8␣ R8A ␤ is functionally active (17,28). This suggests that Arg 8 residue of the CD8␣ subunit is dispensable for the co-receptor function of CD8␣ R8A ␤.…”

Section: Cd8␤ Subunit Of Heterodimeric Cd8␣ E27amentioning

confidence: 99%

“…We recently reported that the Lys 55 in the CDR2-like loop and also Ser 101 and Lys 103 in the CD8␤ CDR3-like loop is critical for the coreceptor activity of CD8␣ R8A ␤, as co-expression of each of these CD8␤ variants with CD8␣ R8A does not lead to detectable co-receptor activity (28). In light of the observation that heterodimeric CD8␣ R8A ␤ is functionally active (17), we questioned whether each of these CD8␤ variants can form a functional coreceptor with WT CD8␣.…”

Section: R8amentioning

confidence: 99%

CD8αβ Has Two Distinct Binding Modes of Interaction with Peptide-Major Histocompatibility Complex Class I

Chang

Tan

Hsu

2006

Journal of Biological Chemistry

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Interaction of CD8 (CD8␣␣ or CD8␣␤) with the peptide-major histocompatibility complex (MHC) class I (pMHCI) is critical for the development and function of cytolytic T cells. Although the crystal structure of CD8␣␣⅐pMHCI complex revealed that two symmetric CD8␣ subunits interact with pMHCI asymmetrically, with one subunit engaged in more extensive interaction than the other, the details of the interaction between the CD8␣␤ heterodimer and pMHCI remained unknown. The Ig-like domains of mouse CD8␣␤ and CD8␣␣ are similar in the size, shape, and surface electrostatic potential of their pMHCI-binding regions, suggesting that their interactions with pMHCI could be very similar. Indeed, we found that the CD8␣ variants CD8␣ R8A and CD8␣ E27A, which were functionally inactive as homodimers, could form an active co-receptor with wildtype (WT) CD8␤ as a CD8␣ R8A ␤ or CD8␣ E27A ␤ heterodimer. We also identified CD8␤ variants that could form active receptors with WT CD8␣ but not with CD8␣R8A . This observation is consistent with the notion that the CD8␤ subunit may replace either CD8␣ subunit in CD8␣␣⅐pMHCI complex. In addition, we showed that both anti-CD8␣ and anti-CD8␤ antibodies were unable to completely block the co-receptor activity of WT CD8␣␤. We propose that CD8␣␤ binds to pMHCI in at least two distinguishable orientations.CD8 is a co-receptor that enhances the presentation of peptide antigen complexed with MHC 2 class I molecule (pMHCI) to the T-cell receptor (1-3). Cell-surface CD8 is assembled as either CD8␣␣ homodimers or CD8␣␤ heterodimers (4 -6). Although CD8␣␣ and CD8␣␤ are structurally similar (7), they differ in tissue distribution, ligand specificity, and efficiency of antigen presentation (8, 9). Although CD8␣␤ is expressed primarily on the surface of ␣␤TCR ϩ thymocytes and peripheral T cells, CD8␣␣ has a much broader expression pattern, including the ␣␤TCR ϩ and ␥␦TCR ϩ intestinal intraepithelial lymphocytes, natural killer cells, and dendritic cells (9 -11). CD8␣␤ has been shown to be a more efficient co-receptor than CD8␣␣ for presentation of a given antigen (12-14). However, the underlying mechanism for the enhanced efficiency is not well understood. Both the extracellular domain and the cytoplasmic tail of the CD8␤ subunit have been implicated in providing increased efficiency of CD8␣␤ (12-16). We reported previously that the extracellular domain of the CD8␤ subunit is critical for this enhanced efficiency (14) and that introduction of the CD8␤ stalk region is sufficient to confer a CD8␣␤-like co-receptor efficiency to the CD8␣␣ homodimer (17). In addition, the sialylation of the O-linked glycans in the CD8␤ stalk region is differentiation stage-dependent and may modulate the intrinsic activity of CD8␣␤ during the transition from double-positive (CD4 ϩ CD8 ϩ ) to single-positive (CD8 ϩ ) T cells (18,19). It was also reported that palmitoylation of a membrane-proximal cysteine residue in the cytoplasmic tail of CD8␤ during T-cell activation facilitates partition of CD8␣␤ heterodimers into lipid rafts,...

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Topology of T cell receptor-peptide/class I MHC interaction defined by charge reversal complementation and functional analysis

Cited by 39 publications

References 76 publications

Altered Peptide Ligand-Mediated TCR Antagonism Can Be Modulated by a Change in a Single Amino Acid Residue Within the CDR3β of an MHC Class I-Restricted TCR

Altered Peptide Ligand-Mediated TCR Antagonism Can Be Modulated by a Change in a Single Amino Acid Residue Within the CDR3β of an MHC Class I-Restricted TCR

Phage‐displayed libraries of peptide/major histocompatibility complexes

CD8αβ Has Two Distinct Binding Modes of Interaction with Peptide-Major Histocompatibility Complex Class I

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