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

Melissa J Rist, Kelly M Hibbert, Nathan P Croft, Corey Smith, Michelle A Neller, Jacqueline M Burrows, John J Miles, Anthony W Purcell, Jamie Rossjohn, Stephanie Gras, Scott R Burrows

Research output: Contribution to journalArticleResearchpeer-review

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.
Original languageEnglish
Pages (from-to)4668 - 4675
Number of pages8
JournalJournal of Immunology
Volume194
Issue number10
DOIs
Publication statusPublished - 2015

Cite this

Rist, Melissa J ; Hibbert, Kelly M ; Croft, Nathan P ; Smith, Corey ; Neller, Michelle A ; Burrows, Jacqueline M ; Miles, John J ; Purcell, Anthony W ; Rossjohn, Jamie ; Gras, Stephanie ; Burrows, Scott R. / T cell cross-reactivity between a highly immunogenic EBV epitope and a self-peptide naturally presented by HLA-B*18:01+ cells. In: Journal of Immunology. 2015 ; Vol. 194, No. 10. pp. 4668 - 4675.
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title = "T cell cross-reactivity between a highly immunogenic EBV epitope and a self-peptide naturally presented by HLA-B*18:01+ cells",
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.",
author = "Rist, {Melissa J} and Hibbert, {Kelly M} and Croft, {Nathan P} and Corey Smith and Neller, {Michelle A} and Burrows, {Jacqueline M} and Miles, {John J} and Purcell, {Anthony W} and Jamie Rossjohn and Stephanie Gras and Burrows, {Scott R}",
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language = "English",
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T cell cross-reactivity between a highly immunogenic EBV epitope and a self-peptide naturally presented by HLA-B*18:01+ cells. / Rist, Melissa J; Hibbert, Kelly M; Croft, Nathan P; Smith, Corey; Neller, Michelle A; Burrows, Jacqueline M; Miles, John J; Purcell, Anthony W; Rossjohn, Jamie; Gras, Stephanie; Burrows, Scott R.

In: Journal of Immunology, Vol. 194, No. 10, 2015, p. 4668 - 4675.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Rist, Melissa J

AU - Hibbert, Kelly M

AU - Croft, Nathan P

AU - Smith, Corey

AU - Neller, Michelle A

AU - Burrows, Jacqueline M

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AU - Gras, Stephanie

AU - Burrows, Scott R

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