TCR-MHC docking orientation: natural selection, or thymic selection?

Collins, Edward J.; Riddle, David S.

doi:10.1007/s12026-008-8040-2

Cited by 32 publications

(35 citation statements)

References 133 publications

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“…Variable domain orientation may be one example of a structural property that the TCR has evolved to enhance its ability to recognise the MHC. Alternatively, such properties may not be encoded on the genome but instead selected for during thymic education of T-cells [55]. Therefore, wider ranges of Vβ-Vα orientations may be possible but only particular conformations are chosen as they are structurally compatible with MHC and co-receptor interactions [56].…”

Section: Discussionmentioning

confidence: 99%

Examining Variable Domain Orientations in Antigen Receptors Gives Insight into TCR-Like Antibody Design

et al. 2014

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The variable domains of antibodies and T-Cell receptors (TCRs) share similar structures. Both molecules act as sensors for the immune system but recognise their respective antigens in different ways. Antibodies bind to a diverse set of antigenic shapes whilst TCRs only recognise linear peptides presented by a major histocompatibility complex (MHC). The antigen specificity and affinity of both receptors is determined primarily by the sequence and structure of their complementarity determining regions (CDRs). In antibodies the binding site is also known to be affected by the relative orientation of the variable domains, VH and VL. Here, the corresponding property for TCRs, the Vβ-Vα orientation, is investigated and compared with that of antibodies. We find that TCR and antibody orientations are distinct. General antibody orientations are found to be incompatible with binding to the MHC in a canonical TCR-like mode. Finally, factors that cause the orientation of TCRs and antibodies to be different are investigated. Packing of the long Vα CDR3 in the domain-domain interface is found to be influential. In antibodies, a similar packing affect can be achieved using a bulky residue at IMGT position 50 on the VH domain. Along with IMGT VH 50, other positions are identified that may help to promote a TCR-like orientation in antibodies. These positions should provide useful considerations in the engineering of therapeutic TCR-like antibodies.

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Section: Discussionmentioning

confidence: 99%

Examining Variable Domain Orientations in Antigen Receptors Gives Insight into TCR-Like Antibody Design

et al. 2014

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“…This includes germline-MHC interactions that are shared in interfaces formed with multiple Vα 12-2 TCRs 29,30 . The extent to which evolution has influenced interactions between TCR germline loops and MHC proteins is controversial 34,35 . As discussed above though, weak interactions do not necessarily imply a lack of specificity.…”

Section: Discussionmentioning

confidence: 99%

The basis for limited specificity and MHC restriction in a T cell receptor interface

et al. 2013

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αβ T cell receptors (TCRs) recognize peptides presented by major histocompatibility complex (MHC) proteins using multiple complementarity determining region (CDR) loops. TCRs display an array of poorly understood recognition properties, including specificity, cross-reactivity, and MHC restriction. Here we report a comprehensive thermodynamic deconstruction of the interaction between the A6 TCR and the Tax peptide presented by the class I MHC HLA-A*0201, uncovering the physical basis for the receptor's recognition properties. Broadly, our findings are in conflict with widely-held generalities regarding TCR recognition, such as the relative contributions of central and peripheral peptide residues and the roles of the hypervariable and germline CDR loops in engaging peptide and MHC. Instead we find that the recognition properties of the receptor emerge from the need to engage the composite peptide/MHC surface, with the receptor utilizing its CDR loops in a cooperative fashion such that specificity, cross-reactivity, and MHC restriction are inextricably linked.

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“…Thus variants that make the best NK cell response are unlikely to make the best CD8 T cell responses, and vice versa. Although MHC class I have interacted with αβTCR for > 400 million years (85), their interactions with variable KIR3DL emerged much more recently, during the 45–82 million years since separation of simian and prosimian ancestors (32, 86, 87). Thus KIR first interacted with forms of MHC class I that had been selected for their capacity to present antigens to T cells.…”

Section: Discussionmentioning

confidence: 99%

Coevolution of Killer Cell Ig-Like Receptors with HLA-C To Become the Major Variable Regulators of Human NK Cells

Aguilar

Guethlein

Adams

et al. 2010

The Journal of Immunology

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Interactions between HLA class I and killer cell immunoglobulin-like receptors (KIR) diversify human NK cell responses. Dominant KIR ligands are the C1 and C2 epitopes of MHC-C, a young locus restricted to humans and great apes. C1 and C1-specific KIR evolved first, being present in orangutan and functionally like their human counterparts. Orangutans lack C2 and C2-specific KIR, but have a unique C1+C2 specific KIR that binds equally to C1 and C2. Such a receptor was likely the mechanism by which C2-KIR interaction evolved from C1-KIR while avoiding a non-functional intermediate: either orphan receptor or ligand. Orangutan inhibitory MHC-C reactive KIR pair with activating receptors of identical avidity and specificity, contrasting with the selective attenuation of human activating KIR. The orangutan C1-specific KIR reacts or cross-reacts with all four polymorphic epitopes (C1, C2, Bw4, and A3/11) recognized by human KIR, revealing their structural commonality. Saturation mutagenesis at specificity-determining position 44, demonstrates that KIR are inherently restricted to binding just these four epitopes, either individually or in combination. This restriction frees the majority of HLA-A and –B variants to be dedicated T-cell receptor ligands, not subject to conflicting pressures from the NK cell and T cell arms of the immune response.

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TCR-MHC docking orientation: natural selection, or thymic selection?

Cited by 32 publications

References 133 publications

Examining Variable Domain Orientations in Antigen Receptors Gives Insight into TCR-Like Antibody Design

Examining Variable Domain Orientations in Antigen Receptors Gives Insight into TCR-Like Antibody Design

The basis for limited specificity and MHC restriction in a T cell receptor interface

Coevolution of Killer Cell Ig-Like Receptors with HLA-C To Become the Major Variable Regulators of Human NK Cells

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