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. 2012 Dec 11;109(50):E3483-92.
doi: 10.1073/pnas.1207896109. Epub 2012 Nov 16.

Structural features underlying T-cell receptor sensitivity to concealed MHC class I micropolymorphisms

Affiliations

Structural features underlying T-cell receptor sensitivity to concealed MHC class I micropolymorphisms

Guillaume B Stewart-Jones et al. Proc Natl Acad Sci U S A. .

Abstract

Polymorphic differences distinguishing MHC class I subtypes often permit the presentation of shared epitopes in conformationally identical formats but can affect T-cell repertoire selection, differentially impacting autoimmune susceptibilities and viral clearance in vivo. The molecular mechanisms underlying this effect are not well understood. We performed structural, thermodynamic, and functional analyses of a conserved T-cell receptor (TCR) which is frequently expanded in response to a HIV-1 epitope when presented by HLA-B*5701 but is not selected by HLA-B*5703, which differs from HLA-B*5701 by two concealed polymorphisms. Our findings illustrate that although both HLA-B*57 subtypes display the epitope in structurally conserved formats, the impact of their polymorphic differences occurs directly as a consequence of TCR ligation, primarily because of peptide adjustments required for TCR binding, which involves the interplay of polymorphic residues and water molecules. These minor differences culminate in subtype-specific differential TCR-binding kinetics and cellular function. Our data demonstrate a potential mechanism whereby the most subtle MHC class I micropolymorphisms can influence TCR use and highlight their implications for disease outcomes.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Structure of the AGA1-HLA-B*5703-KF11 complex. (A) Overview of the AGA1-HLA-B*5703-KF11 complex, the TCR α-chain (cyan), the TCR β-chain (magenta), the HLA-B*5703 heavy chain (gray), β2-microglobulin (β2-m) (orange), and the KF11 peptide (yellow). (B) Positions of CDR loops on HLA-B*5703-KF11. The α-helices of HLA-B*5703 (gray) and CDR1α (red), CDR2α (green), CDR3α (blue), CDR1β (magenta), CDR2β (orange), and CDR3β (cyan) are shown. (C) Surface representation of the AGA1 TCR residues contacting pMHC, colored as in B. (D) Surface representation of pMHC residues contacting AGA1 TCR CDR loops, colored as in B. (E) Surface representation of B*5703 (gray) and KF11 peptide (yellow) and the three CDR loops showing the Tyr side chains clustering around the peptide bulge, colored as described in B.
Fig. 2.
Fig. 2.
KF11 peptide structures in HLA-B*5703 and HLA-B*5701. (A) Profile view of superimposition via the HLA peptide-binding grooves for KF11 peptides in HLA-B*57, showing conformational change between the unliganded peptide structures, with HLA-B*5701-KF11 (orange), HLA-B*5703-KF11 (yellow), and AGA1 TCR-bound peptide (magenta) illustrated. The MHC α1 helix is shown in gray. (B) Top view of A, showing both MHC α1 and α2 helices (gray). (CE) Refined peptide structures and polymorphic side chains at MHC position 114 and 116 and associated 2fo-fc electron density maps are shown for the HLA-B*5701-KF11 (C), HLA-B*5703-KF11 (D), and HLA-B*5703-KF11-AGA1 TCR (E) complexes. (F) MHC superimposition showing the position of unliganded HLA-B*5703 KF11 peptide (yellow) versus AGA1 TCR-bound peptide (magenta) water molecules displaced on TCR binding HLA-B*5703-KF11 (red spheres) and the positions of the three CDR loops and associated Tyr side chains, colored as described in Fig.1A.
Fig. 3.
Fig. 3.
TCR CDR loop interactions with HLA-B*5703-KF11. (A) The CDR3α loop (blue), HLA-B*5703 (gray), KF11 peptide (yellow), and hydrogen bonds (dashed lines) are displayed. (B) Alternative view of A. (C) The CDR2α loop (green), HLA-B*5703 (gray), KF11 peptide (yellow), and hydrogen bonds (dashed lines) are shown. (D) The CDR3α and CDR3β loops (blue and cyan, respectively), HLA-B*5703 (gray), KF11 peptide (magenta), and hydrogen bonds between loops (dashed lines) are shown. (E) The CDR3β loop (cyan), HLA-B*5703 (gray), KF11 peptide (yellow), and hydrogen bonds (dashed lines) are shown. (F) The CDR1α loop (red), HLA-B*5703 (gray), KF11 peptide (yellow), and hydrogen bonds (dashed lines) are illustrated. Residues are identified as one-letter amino acids followed by the AGA1 TCR chain (α or β) or peptide (p).
Fig. 4.
Fig. 4.
Ordered water molecules and conformational changes on TCR binding. (A) The re-refined unliganded HLA-B*5703-KF11 structure: water molecules (red spheres) contoured with 2fo-fc electron density at 1σ, HLA-B*5703 (gray), KF11 peptide (yellow), and hydrogen bonds (dashed lines). (B) Unliganded HLA-B*5701-KF11 structure: water molecules (red spheres) contoured with 2fo-fc electron density at 1σ, HLA-B*5701 (gray), KF11 peptide (yellow), and hydrogen bonds (dashed lines). (C) HLA-B*5703-KF11-AGA1 TCR complex structure (magenta) superimposed with HLA-B*5703-KF11, colored as in A. Peptide P9 side chain from the TCR complex sterically clashes with water molecule A2193 and polymorphic MHC Y116, reorienting Y116 by some 15° and thereby making a new hydrogen bond to the N114 side chain (magenta dashed line). (D) HLA-B*5703-KF11-TCR complex structure (magenta) superimposed with HLA-B*5701-KF11, colored as in B. The peptide P9 side chain from the TCR complex is predicted to sterically clash with water molecule Z48 that hydrogen bonds to Y74.
Fig. 5.
Fig. 5.
Enhanced sensitization of AGA1-expressing T-cell clones by B*5701-expressing antigen-presenting cells. (A and B) AGA1-expressing CD8+ T-cell clones and clones demonstrating KF11 specificity but expressing diverse αβTCR pairs (Insets) were tested for their ability to secrete IFN-γ in response to peptide-pulsed HLA-B*5701- (red) and HLA-B*5703-expressing (teal) BCL targets, over a 10-fold peptide titration from 10–0.01 μM (A) and IIIB gag rVV-infected targets at effector:target (E:T) ratios of 0.025:1 and 0.0125:1 (B). CD8+ T-cell responses are reported as the number of spot forming cells (SFC) per 500 cell input; values shown are median ± SEM. (C) Expression of the CD107a/b LAMP markers in response to peptide-pulsed HLA-B*5701 and B*5703 (1 and 10 μM, respectively) at an E:T ratio of 2:1, by flow cytometry analysis. CD8+ T cells were gated as a function of both positive (forward scatter versus side scatter) and negative (forward scatter versus CD8) gating. CD8+ cells are indicated along the y-axis and CD107a/b expression along the x-axis. A representative of three independent experiments (each performed in triplicate) is presented.
Fig. P1.
Fig. P1.
Events subsequent to TCR binding help explain the preference of the AGA1 TCR for HLA-B*5701-KF11. (A) Superimposition of the HLA-B*5703-KF11 (yellow peptide) and AGA1-bound HLA-B*5703-KF11 (magenta peptide) structures illustrates repositioning of the peptide Pro9 side chain following TCR binding, with reorientation of Tyr116 toward Asn114. (HLA-B*5703 is shown in gray, hydrogen bonds are indicated by dashed lines, and water molecules are indicated by red spheres). (B) When modeled with HLA-B*5701-KF11, AGA1-driven reorientation of Pro9 is considered unlikely to impact the smaller Ser116 side chain. (C) The thermodynamic signatures relating to the activation entropy (TΔSdiss), enthalpy (ΔHdiss), and free energy of TCR dissociation (ΔGdiss) are similar for HLA-B*5703 and single-mutant hybrids but differ for HLA-B*5701 [differences relative to the B*5701-KF11-AGA1 (Δ)].

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