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Open AccessArticle

Unusual Placement of an EBV Epitope into the Groove of the Ankylosing Spondylitis-Associated HLA-B27 Allele Allows CD8+ T Cell Activation

1
Department of Biology and Biotechnology ‘Charles Darwin’, Sapienza University of Rome, 00185 Rome, Italy
2
Department of Chemistry, Sapienza University of Rome, 00185 Rome, Italy
3
Division of Clinical Immunology and Rheumatology, Department of Biotechnology and Medical Surgical Sciences, Sapienza University of Rome, 00185 Rome, Italy
4
Rheumatology Unit, Department of Medical Sciences and Public Health, University and AOU of Cagliari, Monserrato, 09042 Cagliari, Italy
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Cells 2019, 8(6), 572; https://doi.org/10.3390/cells8060572
Received: 2 April 2019 / Revised: 6 June 2019 / Accepted: 8 June 2019 / Published: 11 June 2019
(This article belongs to the Special Issue Major Histocompatibility Complex (MHC) in Health and Disease)
The human leukocyte antigen HLA-B27 is a strong risk factor for Ankylosing Spondylitis (AS), an immune-mediated disorder affecting axial skeleton and sacroiliac joints. Additionally, evidence exists sustaining a strong protective role for HLA-B27 in viral infections. These two aspects could stem from common molecular mechanisms. Recently, we have found that the HLA-B*2705 presents an EBV epitope (pEBNA3A-RPPIFIRRL), lacking the canonical B27 binding motif but known as immunodominant in the HLA-B7 context of presentation. Notably, 69% of B*2705 carriers, mostly patients with AS, possess B*2705-restricted, pEBNA3A-specific CD8+ T cells. Contrarily, the non-AS-associated B*2709 allele, distinguished from the B*2705 by the single His116Asp polymorphism, is unable to display this peptide and, accordingly, B*2709 healthy subjects do not unleash specific T cell responses. Herein, we investigated whether the reactivity towards pEBNA3A could be a side effect of the recognition of the natural longer peptide (pKEBNA3A) having the classical B27 consensus (KRPPIFIRRL). The stimulation of PBMC from B*2705 positive patients with AS in parallel with both pEBNA3A and pKEBNA3A did not allow to reach an unambiguous conclusion since the differences in the magnitude of the response measured as percentage of IFNγ-producing CD8+ T cells were not statistically significant. Interestingly, computational analysis suggested a structural shift of pEBNA3A as well as of pKEBNA3A into the B27 grooves, leaving the A pocket partially unfilled. To our knowledge this is the first report of a viral peptide: HLA-B27 complex recognized by TCRs in spite of a partially empty groove. This implies a rethinking of the actual B27 immunopeptidome crucial for viral immune-surveillance and autoimmunity. View Full-Text
Keywords: HLA-B27; viral peptides; computational analysis; ankylosing spondylitis HLA-B27; viral peptides; computational analysis; ankylosing spondylitis
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Tedeschi, V.; Alba, J.; Paladini, F.; Paroli, M.; Cauli, A.; Mathieu, A.; Sorrentino, R.; D’Abramo, M.; Fiorillo, M.T. Unusual Placement of an EBV Epitope into the Groove of the Ankylosing Spondylitis-Associated HLA-B27 Allele Allows CD8+ T Cell Activation. Cells 2019, 8, 572.

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