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Conformational melding permits a conserved binding geometry in TCR recognition of foreign and self molecular mimics.

ABSTRACT: Molecular mimicry between foreign and self Ags is a mechanism of TCR cross-reactivity and is thought to contribute to the development of autoimmunity. The ?? TCR A6 recognizes the foreign Ag Tax from the human T cell leukemia virus-1 when presented by the class I MHC HLA-A2. In a possible link with the autoimmune disease human T cell leukemia virus-1-associated myelopathy/tropical spastic paraparesis, A6 also recognizes a self peptide from the neuronal protein HuD in the context of HLA-A2. We found in our study that the complexes of the HuD and Tax epitopes with HLA-A2 are close but imperfect structural mimics and that in contrast with other recent structures of TCRs with self Ags, A6 engages the HuD Ag with the same traditional binding mode used to engage Tax. Although peptide and MHC conformational changes are needed for recognition of HuD but not Tax and the difference of a single hydroxyl triggers an altered TCR loop conformation, TCR affinity toward HuD is still within the range believed to result in negative selection. Probing further, we found that the HuD-HLA-A2 complex is only weakly stable. Overall, these findings help clarify how molecular mimicry can drive self/nonself cross-reactivity and illustrate how low peptide-MHC stability can permit the survival of T cells expressing self-reactive TCRs that nonetheless bind with a traditional binding mode.

SUBMITTER: Borbulevych OY

PROVIDER: S-EPMC3076315 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Conformational melding permits a conserved binding geometry in TCR recognition of foreign and self molecular mimics.

Borbulevych Oleg Y OY Piepenbrink Kurt H KH Baker Brian M BM

Journal of immunology (Baltimore, Md. : 1950) 20110131 5

Molecular mimicry between foreign and self Ags is a mechanism of TCR cross-reactivity and is thought to contribute to the development of autoimmunity. The αβ TCR A6 recognizes the foreign Ag Tax from the human T cell leukemia virus-1 when presented by the class I MHC HLA-A2. In a possible link with the autoimmune disease human T cell leukemia virus-1-associated myelopathy/tropical spastic paraparesis, A6 also recognizes a self peptide from the neuronal protein HuD in the context of HLA-A2. We fo ...[more]

PMID: 21282516

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Project description:Given the limited set of T cell receptor (TCR) V genes that are used to create TCRs that are reactive to different ligands, such as major histocompatibility complex (MHC) class I, MHC class II, and MHC-like proteins (for example, MIC molecules and CD1 molecules), the V?1 segment can be rearranged with D?-J?-C? or J?-C? segments to form classical ??TCRs or uncommon ??TCRs using a V?1 segment (?/??TCR). Here we have determined two complex structures of the ?/??TCRs (S19-2 and TU55) bound to different locus-disparate MHC class I molecules with HIV peptides (HLA-A*2402-Nef138-10 and HLA-B*3501-Pol448-9). The overall binding modes resemble those of classical ??TCRs but display a strong tilt binding geometry of the V?1 domain toward the HLA ?1 helix, due to a conserved extensive interaction between the CDR1? loop and the N-terminal region of the ?1 helix (mainly in position 62). The aromatic amino acids of the CDR1? loop exploit different conformations ("aromatic ladder" or "aromatic hairpin") to accommodate distinct MHC helical scaffolds. This tolerance helps to explain how a particular TCR V region can similarly dock onto multiple MHC molecules and thus may potentially explain the nature of TCR cross-reactivity. In addition, the length of the CDR3? loop could affect the extent of tilt binding of the V?1 domain, and adaptively, the pairing V? domains adjust their mass centers to generate differential MHC contacts, hence probably ensuring TCR specificity for a certain peptide-MHC class I (pMHC-I). Our data have provided further structural insights into the TCR recognition of classical pMHC-I molecules, unifying cross-reactivity and specificity.IMPORTANCE The specificity of ?? T cell recognition is determined by the CDR loops of the ??TCR, and the general mode of binding of ??TCRs to pMHC has been established over the last decade. Due to the intrinsic genomic structure of the TCR ?/? chain locus, some V? segments can rearrange with the C? segment, forming a hybrid V?C?V?C? TCR, the ?/??TCR. However, the basis for the molecular recognition of such TCRs of their ligands is elusive. Here an ??TCR using the V?1 segment, S19-2, was isolated from an HIV-infected patient in an HLA-A*24:02-restricted manner. We then solved the crystal structures of the S19-2 TCR and another ?/??TCR, TU55, bound to their respective ligands, revealing a conserved V?1 binding feature. Further binding kinetics analysis revealed that the S19-2 and TU55 TCRs bind pHLA very tightly and in a long-lasting manner. Our results illustrate the mode of binding of a TCR using the V?1 segment to its ligand, virus-derived pHLA.

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Conformational melding permits a conserved binding geometry in TCR recognition of foreign and self molecular mimics.

Publications

Conformational melding permits a conserved binding geometry in TCR recognition of foreign and self molecular mimics.

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