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. 2005 Sep 7;24(17):2968-79.
doi: 10.1038/sj.emboj.7600771. Epub 2005 Aug 4.

Structure of a human autoimmune TCR bound to a myelin basic protein self-peptide and a multiple sclerosis-associated MHC class II molecule

Yili Li  1 , Yuping Huang, Jessica Lue, Jacqueline A Quandt, Roland Martin, Roy A Mariuzza
Affiliations

Structure of a human autoimmune TCR bound to a myelin basic protein self-peptide and a multiple sclerosis-associated MHC class II molecule

Yili Li et al. EMBO J. .

Abstract

Multiple sclerosis is mediated by T-cell responses to central nervous system antigens such as myelin basic protein (MBP). To investigate self-peptide/major histocompatibility complex (MHC) recognition and T-cell receptor (TCR) degeneracy, we determined the crystal structure, at 2.8 A resolution, of an autoimmune TCR (3A6) bound to an MBP self-peptide and the multiple sclerosis-associated MHC class II molecule, human leukocyte antigen (HLA)-DR2a. The complex reveals that 3A6 primarily recognizes the N-terminal portion of MBP, in contrast with antimicrobial and alloreactive TCRs, which focus on the peptide center. Moreover, this binding mode, which may be frequent among autoimmune TCRs, is compatible with a wide range of orientation angles of TCR to peptide/MHC. The interface is characterized by a scarcity of hydrogen bonds between TCR and peptide, and TCR-induced conformational changes in MBP/HLA-DR2a, which likely explain the low observed affinity. Degeneracy of 3A6, manifested by recognition of superagonist peptides bearing substitutions at nearly all TCR-contacting positions, results from the few specific interactions between 3A6 and MBP, allowing optimization of interface complementarity through variations in the peptide.

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Figures

Figure 1
Figure 1
Binding of TCR 3A6 tetramers to MBP/DR2a and K38-27/DR2a complexes. (A) Sensograms showing the binding of 3A6 tetramers at concentrations of 2.3 μM (blue), 1.2 μM (red) and 0.6 μM (green) to HLA-DR2a loaded with MBP 89–101 (VHFFKNIVTPRTP). HLA-DR2a was immobilized on a BIAcore SA chip by injecting 5 μl of biotin-HLA-DR2a (0.1 μM) over the chip. (B) Binding of 3A6 tetramers to HLA-DR2a loaded with an irrelevant peptide. (C) Binding of 3A6 tetramers to HLA-DR2a loaded with K38-27 (WFKLTTTKL), a superagonist peptide (Hemmer et al, 2000).
Figure 2
Figure 2
Electron density in the interface of the 3A6/MBP/HLA-DR2a complex. Density from the final 2Fo−Fc map at 2.8 Å resolution showing the N-terminal region of the MBP peptide. TCR is yellow, peptide is red and MHC is cyan. Contours are at 1σ.
Figure 3
Figure 3
3A6/MBP/HLA-DR2a complex and comparison with other TCR/peptide/MHC class II complexes. (A) Side view of the 3A6/MBP/DR2a complex. TCR α-chain is yellow and β-chain is gray; peptide is magenta; MHC α-chain is cyan and β-chain is green. (B) Top view of the 3A6/MBP/DR2a complex, compared with (C) the HA1.7/HA/DR1 complex (Hennecke et al, 2000), (D) 172.10/MBP/I-Au complex (Maynard et al, 2005) and (E) Ob.1A12/MBP/DR2b complex (Hahn et al, 2005). Color codes are the same as (A). The central P5 residue of the peptide is represented as a red sphere.
Figure 4
Figure 4
Interactions of TCR 3A6 with HLA-DR2a and the MBP peptide. (A) Interactions of the HLA-DR2a α-chains (cyan) and β-chains (green) with the TCR 3A6 α-chains (yellow) and β-chains (gray). The contact residues are drawn and labeled. Hydrogen bonds are indicated by broken black lines and the MBP peptide is magenta. (B) Interactions of the TCR 3A6 α-chains (yellow) and β-chains (gray) with the MBP peptide (magenta) drawn in a ball-and-stick representation. Contact residues are labeled. The P2 Lys Nζ–O CDR3α Gly94 hydrogen bond is present in only two of the four complex molecules in the asymmetric unit of the crystal.
Figure 5
Figure 5
Position of TCRs along peptide antigen. (A) Ribbon diagram (stereo view) showing the position of the CDR3α (yellow) and CDR3β (gray) loops of 3A6 along the MBP peptide, compared to the position of the corresponding loops of TCRs HA1.7 and 172.10 (CDR3α loops are red; CDR3β loops are blue), upon superposition of the MHC α1β1 modules in the three complexes. The MBP peptide is drawn in a ball-and-stick format; anchor residues are labeled. Carbon atoms are magenta, oxygen atoms are red and nitrogen atoms are blue. (B) Position of the 3A6 CDR3α (yellow) and CDR3β (gray) loops along the MBP peptide, compared to the position of the corresponding loops of TCR Ob.1A12 (CDR3α loop is red; CDR3β loop is blue).
Figure 6
Figure 6
Conformational changes in MBP/HLA-DR2a upon binding TCR 3A6. (A) Top view of the superposition of MBP/HLA-DR2a in unliganded form (green) and in complex with 3A6 (red). 3A6 CDR loops are shown in a stick format. Carbon atoms are yellow, oxygen atoms are red and nitrogen atoms are blue. (B) Comparison of the MBP peptide conformation before (yellow) and after (red) binding to TCR 3A6. (C) Comparison of the MBP peptide conformation before (yellow) and after (red) binding to the superantigen SPE-C (Li et al, 2001). The three C-terminal residues of MBP 89–101 are disordered in the SPE-C/MBP/DR2a structure. (D) Comparison of the MBP/HLA-DR2a surface after (left panel) and before (right panel) binding to 3A6. TCR residues, in particular Asp98β and Arg99β, fit better into pockets on the bound MBP/HLA-DR2a surface (left) than into pockets on the free MBP/HLA-DR2a surface (right). 3A6 residues are shown in a stick format and labeled.
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