T cell cross-reactivity between a highly immunogenic EBV epitope and a self-peptide naturally presented by HLA-B*18:01+ cells

Rist, M. J., Hibbert, K. M., Croft, N. P., Smith, C., Neller, M. A., Burrows, J. M., Miles, John James, Purcell, A. W., Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522, Gras, S. and Burrows, S. R. 2015. T cell cross-reactivity between a highly immunogenic EBV epitope and a self-peptide naturally presented by HLA-B*18:01+ cells. The Journal of Immunology 194 (10) , pp. 4668-4675. 10.4049/jimmunol.1500233

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Abstract

T cell cross-reactivity underpins the molecular mimicry hypothesis in which microbial peptides sharing structural features with host peptides stimulate T cells that cross-react with self-peptides, thereby initiating and/or perpetuating autoimmune disease. EBV represents a potentially important factor in the pathogenesis of several T cell–mediated autoimmune disorders, with molecular mimicry a likely mechanism. In this study, we describe a human self-peptide (DELEIKAY) that is a homolog of a highly immunogenic EBV T cell epitope (SELEIKRY) presented by HLA-B*18:01. This self-peptide was shown to bind stably to HLA-B*18:01, and peptide elution/mass spectrometric studies showed it is naturally presented by this HLA molecule on the surface of human cells. A significant proportion of CD8+ T cells raised from some healthy individuals against this EBV epitope cross-reacted with the self-peptide. A diverse array of TCRs was expressed by the cross-reactive T cells, with variable functional avidity for the self-peptide, including some T cells that appeared to avoid autoreactivity by a narrow margin, with only 10-fold more of the self-peptide required for equivalent activation as compared with the EBV peptide. Structural studies revealed that the self-peptide–HLA-B*18:01 complex is a structural mimic of the EBV peptide–HLA-B*18:01 complex, and that the strong antiviral T cell response is primarily dependent on the alanine/arginine mismatch at position 7. To our knowledge, this is the first report confirming the natural presentation of a self-peptide cross-recognized in the context of self-HLA by EBV-reactive CD8+ T cells. These results illustrate how aberrant immune responses and immunopathological diseases could be generated by EBV infection.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
Publisher:	American Association of Immunologists
ISSN:	0022-1767
Date of Acceptance:	12 March 2015
Last Modified:	10 Jun 2023 01:10
URI:	https://orca.cardiff.ac.uk/id/eprint/84747

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