Abstract
The development of autoimmune disorders is incompletely understood. Inefficient thymic T cell selection against self-peptides presented by major histocompatibility antigens (HLA in humans) may contribute to the emergence of auto-reactive effector cells, and molecular mimicry between foreign and self-peptides could promote T cell cross-reactivity. A pair of class I subtypes, HLA-B2705 and HLA-B2709, have previously been intensely studied, because they are distinguished from each other only by a single amino acid exchange at the floor of the peptide-binding groove, yet are differentially associated with the autoinflammatory disorder ankylosing spondylitis. Using X-ray crystallography in combination with ensemble refinement, we find that the non-disease-associated subtype HLA-B2709, when presenting the self-peptide pGR (RRRWHRWRL), exhibits elevated conformational dynamics, and the complex can also be recognized by T cells. Both features are not observed in case of the sequence-related self-peptide pVIPR (RRKWRRWHL) in complex with this subtype, and T cell cross-reactivity between pGR, pVIPR, and the viral peptide pLMP2 (RRRWRRLTV) is only rarely observed. The disease-associated subtype HLA-B2705, however, exhibits extensive conformational flexibility in case of the three complexes, all of which are also recognized by frequently occurring cross-reactive T cells. A comparison of the structural and dynamic properties of the six HLA-B27 complexes, together with their individual ability to interact with T cells, permits us to correlate the flexibility of HLA-B27 complexes with effector cell reactivity. The results suggest the existence of an inverse relationship between conformational plasticity of peptide-HLA-B27 complexes and the efficiency of negative selection of self-reactive cells within the thymus.
Highlights
The vast majority of autoimmune diseases is associated with HLA class II alleles [1], the first association detected and still one of the strongest found so far is that between the class I gene HLA-B∗27:05 subtype (B∗27) and the autoinflammatory rheumatic disorder ankylosing spondylitis (AS) [2, 3]
We address three issues in particular: (i) Is the extent of peptide dynamics a consequence of display by a particular HLA-B27 subtype? (ii) Does the overall conformational plasticity of a given peptide-HLA-B27 complex allow to correlate this property with cytotoxic T lymphocytes (CTL) reactivity? and (iii) Do the complexes of B2709 displaying pGR, pVIPR, or pLMP2 exhibit a lack of comprehensive molecular mimicry? Together with previously published studies [13,14,15,16, 18] the high resolution structure of pGR-B2709 that we describe here permits to shed light on these questions and indicates that the occurrence of peripheral self-reactive CTL is connected with the conformational plasticity of peptide-HLA-B27 complexes
Conformational plasticity is a prerequisite for the successful interaction of MHC molecules with extra- and intracellular binding partners
Summary
The vast majority of autoimmune diseases is associated with HLA class II alleles [1], the first association detected and still one of the strongest found so far is that between the class I gene HLA-B∗27 and the autoinflammatory rheumatic disorder ankylosing spondylitis (AS) [2, 3]. Not all of the >170 alleles (“subtypes”) of HLA-B∗27 are associated with AS: while the prototypical HLA-B∗27:05 subtype (B∗27:05 in short) is AS-associated, HLA-B∗27:09 (in short, B∗27:09) is not [9]. Both alleles encode a heavy chain (HC) that associates non-covalently with a light chain, β2-microglobulin (β2m), and a self- or foreign peptide. The B2705 and B2709 complexes are distinguished only by an Asp116His exchange within their HC, located on the floor of the peptide binding groove within the F-pocket Comparative studies of these two subtypes can be regarded as promising to understand various aspects of AS pathogenesis
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