Conformational Plasticity of HLA-B27 Molecules Correlates Inversely With Efficiency of Negative T Cell Selection

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.

EULAR study group on ‘MHC-I-opathy’: identifying disease-overarching mechanisms across disciplines and borders

“…According to this theory, predisposing MHC-I molecules may exhibit properties which could cause excessive misfolding and accumulation in the ER, promoting the 'unfolded protein response'. [33][34][35][36][37][38] Studies of (HLA-B*27) transgenic animals and cellular models support this hypothesis, but there is a paucity of translational evidence. [39][40][41][42][43] A third popular hypothesis suggests that the predisposing MHC-I alleles are recognised by KIRs or leucocyte immunoglobulin-like receptors (LILRs) on the cell surface of NK cells.…”

Uncovering the Underworld of Axial Spondyloarthritis

“…It has been suggested that molecular plasticity inversely correlates with the efficiency of negative T cell selection within the thymic medulla. This process may be impaired when the T cells confront a highly flexible binding groove, causing the failure of negative selection against self-peptide [ 17 , 18 ]. The surviving CD8 + T lymphocytes would then recognize these peptides in peripheral tissues, in contrast to what happens in the thymus, due to increased peptide concentration in key peripheral tissues or post-translationally modifications that take place in specific tissues [ 19 ].…”

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“…The nature of the peptidome efficiently bound and presented by HLA-B*27 is highly influenced by the stability of the molecule itself; several studies have described a higher flexibility of HLA-B*27:05, compared to B*27:09, suggesting an intrinsic propensity of this subtype to adopt unconventional conformations, especially in the proximity of the binding groove [ 44 , 45 , 46 ]. Moreover, a recent work by Loll’s research group has suggested that HLA-B*27:05, but not B*27:09, undergoes metal ion-induced conformational alterations that, in turn, could influence the capability of the AS-associated allele to bind suboptimal peptides [ 47 ].…”