(a) Insulin B1–B23 epitope modeled into the α1β1 domain of the HLA-DQ8 heterodimer. It has been shown that CD4+ T cells from type 1 diabetes patients are sensitized to this complex [62]. The insulin peptide is in space-filling form with its atoms colored as follows: carbon, green; oxygen, red; nitrogen, blue; hydrogen, white; sulfur, yellow. The HLA-DQ8 (A1*03:01-B1*03:02) heterodimer is in van der Waals surface representation, colored according to atom charge (red, negative; blue, positive; gray, neutral; partial charges in shades in-between). A few residues from the HLA-DQ molecule in contact with the antigenic peptide are shown via a transparency function in stick form (same color notation as in the peptide with the exception of carbon that is in orange). Modeling and binding studies have shown that the insulin peptide binds to the other three HLA-DQ diabetes-susceptible haplotypes (A1*05:01-B1*02:01, A1*05:01-B1*03:02, A1*03:01-B1*02:01) in an identical register [63]. This view is as seen from the T-cell receptor, which might fit with its symmetry axis in an approximate diagonal fashion with respect to the peptide axis (fitting of TCRs specific for microbial peptides). The few examples of structures of autoimmune TCR in complex with cognate MHC II-peptide complexes reveal an off-diagonal recognition involving mostly the N-terminal half of the peptide and more selective contacts with the MHC II molecule. Molecule drawn from coordinates provided in [136]. (b) TCR view of the complex of HLA-A2, the most frequent Class I allele among Caucasians, with the proinsulin peptide C6–C14 (DLQVGQVEL; anchors in bold). Color code and conventions are as in (a). The peptide shown is part of epitope pool 60 (AEDLQVGQVEL, EDLQVGQVEL, DLQVGQVEL, and LQVGQVEL). All four epitopes should bind well to HLA-A2, with SI < 3 in controls and SI > 3 in 3/6 T1D patients [91]. The epitope depicted was first identified, though not tested on PBMCs of T1D patients in [68]. (c) TCR view of the complex of HLA-A2, with the insulin peptide C6–C15 (DLQVGQVELG, anchors in bold). Color code and conventions are as in (a). This is part of epitope pool 61 (EDLQVGQVELG, DLQVGQVELG, LQVGQVELG, and QVGQVELG). The first three of the epitopes should bind weakly to HLA-A2 and the fourth one hardly at all. It is also possible to have a different register altogether, especially for the last two peptides (LQVGQVELG and QVGQVELG), with SI < 2 in all controls and SI > 3 in 2/6 T1D patients [106]. (d) TCR view of the complex of HLA-A2 with the insulin peptide B5–B14 (HLCGSHLVEA), recently identified as an epitope for HLA-A2 in type 1 diabetes patients of recent onset, with the very sensitive tetramer labeling using the quantum dot technique [71]. This peptide belongs to pool 30 [106] (QHLCGSHLVEA, HLCGSHLVEA, LCGSHLVEA), where it has also shown reactivity. Note that this peptide will also bind very strongly to the protective allele HLA-DQB1*06:02, as well as to the slightly susceptible allele HLA-DQB1*06:04, in the same core nonamer register B6–B14 [139, 140].
