Structural basis for the killing of human beta cells by CD8+ T cells in type 1 diabetes

Anna M Bulek, David K Cole, Ania Skowera, Garry Dolton, Stephanie Gras, Florian Madura, Anna Fuller, John J Miles, Emma Gostick, David A Price, Jan W Drijfhout, Robin R Knight, Guo C Huang, Nikolai Lissin, Peter E Molloy, Linda Wooldridge, Bent K Jakobsen, Jamie Rossjohn, Mark Peakman, Pierre J RizkallahAndrew K Sewell

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Abstract

The structural characteristics of the engagement of major histocompatibility complex (MHC) class II-restricted self antigens by autoreactive T cell antigen receptors (TCRs) is established, but how autoimmune TCRs interact with complexes of self peptide and MHC class I has been unclear. Here we examined how CD8(+) T cells kill human islet beta cells in type 1 diabetes via recognition of a human leukocyte antigen HLA-A*0201-restricted glucose-sensitive preproinsulin peptide by the autoreactive TCR 1E6. Rigid lock-and-key binding underpinned the 1E6-HLA-A*0201-peptide interaction, whereby 1E6 docked similarly to most MHC class I-restricted TCRs. However, this interaction was extraordinarily weak because of limited contacts with MHC class I. TCR binding was highly peptide centric, dominated by two residues of the complementarity-determining region 3 (CDR3) loops that acted as an aromatic-cap over the complex of peptide and MHC class I (pMHCI). Thus, highly focused peptide-centric interactions associated with suboptimal TCR-pMHCI binding affinities might lead to thymic escape and potential CD8(+) T cell-mediated autoreactivity.
Original languageEnglish
Pages (from-to)283-289
Number of pages7
JournalNature Immunology
Volume13
Issue number3
DOIs
Publication statusPublished - 2012

Cite this

Bulek, A. M., Cole, D. K., Skowera, A., Dolton, G., Gras, S., Madura, F., ... Sewell, A. K. (2012). Structural basis for the killing of human beta cells by CD8+ T cells in type 1 diabetes. Nature Immunology, 13(3), 283-289. https://doi.org/10.1038/ni.2206
Bulek, Anna M ; Cole, David K ; Skowera, Ania ; Dolton, Garry ; Gras, Stephanie ; Madura, Florian ; Fuller, Anna ; Miles, John J ; Gostick, Emma ; Price, David A ; Drijfhout, Jan W ; Knight, Robin R ; Huang, Guo C ; Lissin, Nikolai ; Molloy, Peter E ; Wooldridge, Linda ; Jakobsen, Bent K ; Rossjohn, Jamie ; Peakman, Mark ; Rizkallah, Pierre J ; Sewell, Andrew K. / Structural basis for the killing of human beta cells by CD8+ T cells in type 1 diabetes. In: Nature Immunology. 2012 ; Vol. 13, No. 3. pp. 283-289.
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abstract = "The structural characteristics of the engagement of major histocompatibility complex (MHC) class II-restricted self antigens by autoreactive T cell antigen receptors (TCRs) is established, but how autoimmune TCRs interact with complexes of self peptide and MHC class I has been unclear. Here we examined how CD8(+) T cells kill human islet beta cells in type 1 diabetes via recognition of a human leukocyte antigen HLA-A*0201-restricted glucose-sensitive preproinsulin peptide by the autoreactive TCR 1E6. Rigid lock-and-key binding underpinned the 1E6-HLA-A*0201-peptide interaction, whereby 1E6 docked similarly to most MHC class I-restricted TCRs. However, this interaction was extraordinarily weak because of limited contacts with MHC class I. TCR binding was highly peptide centric, dominated by two residues of the complementarity-determining region 3 (CDR3) loops that acted as an aromatic-cap over the complex of peptide and MHC class I (pMHCI). Thus, highly focused peptide-centric interactions associated with suboptimal TCR-pMHCI binding affinities might lead to thymic escape and potential CD8(+) T cell-mediated autoreactivity.",
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Bulek, AM, Cole, DK, Skowera, A, Dolton, G, Gras, S, Madura, F, Fuller, A, Miles, JJ, Gostick, E, Price, DA, Drijfhout, JW, Knight, RR, Huang, GC, Lissin, N, Molloy, PE, Wooldridge, L, Jakobsen, BK, Rossjohn, J, Peakman, M, Rizkallah, PJ & Sewell, AK 2012, 'Structural basis for the killing of human beta cells by CD8+ T cells in type 1 diabetes', Nature Immunology, vol. 13, no. 3, pp. 283-289. https://doi.org/10.1038/ni.2206

Structural basis for the killing of human beta cells by CD8+ T cells in type 1 diabetes. / Bulek, Anna M; Cole, David K; Skowera, Ania; Dolton, Garry; Gras, Stephanie; Madura, Florian; Fuller, Anna; Miles, John J; Gostick, Emma; Price, David A; Drijfhout, Jan W; Knight, Robin R; Huang, Guo C; Lissin, Nikolai; Molloy, Peter E; Wooldridge, Linda; Jakobsen, Bent K; Rossjohn, Jamie; Peakman, Mark; Rizkallah, Pierre J; Sewell, Andrew K.

In: Nature Immunology, Vol. 13, No. 3, 2012, p. 283-289.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Structural basis for the killing of human beta cells by CD8+ T cells in type 1 diabetes

AU - Bulek, Anna M

AU - Cole, David K

AU - Skowera, Ania

AU - Dolton, Garry

AU - Gras, Stephanie

AU - Madura, Florian

AU - Fuller, Anna

AU - Miles, John J

AU - Gostick, Emma

AU - Price, David A

AU - Drijfhout, Jan W

AU - Knight, Robin R

AU - Huang, Guo C

AU - Lissin, Nikolai

AU - Molloy, Peter E

AU - Wooldridge, Linda

AU - Jakobsen, Bent K

AU - Rossjohn, Jamie

AU - Peakman, Mark

AU - Rizkallah, Pierre J

AU - Sewell, Andrew K

PY - 2012

Y1 - 2012

N2 - The structural characteristics of the engagement of major histocompatibility complex (MHC) class II-restricted self antigens by autoreactive T cell antigen receptors (TCRs) is established, but how autoimmune TCRs interact with complexes of self peptide and MHC class I has been unclear. Here we examined how CD8(+) T cells kill human islet beta cells in type 1 diabetes via recognition of a human leukocyte antigen HLA-A*0201-restricted glucose-sensitive preproinsulin peptide by the autoreactive TCR 1E6. Rigid lock-and-key binding underpinned the 1E6-HLA-A*0201-peptide interaction, whereby 1E6 docked similarly to most MHC class I-restricted TCRs. However, this interaction was extraordinarily weak because of limited contacts with MHC class I. TCR binding was highly peptide centric, dominated by two residues of the complementarity-determining region 3 (CDR3) loops that acted as an aromatic-cap over the complex of peptide and MHC class I (pMHCI). Thus, highly focused peptide-centric interactions associated with suboptimal TCR-pMHCI binding affinities might lead to thymic escape and potential CD8(+) T cell-mediated autoreactivity.

AB - The structural characteristics of the engagement of major histocompatibility complex (MHC) class II-restricted self antigens by autoreactive T cell antigen receptors (TCRs) is established, but how autoimmune TCRs interact with complexes of self peptide and MHC class I has been unclear. Here we examined how CD8(+) T cells kill human islet beta cells in type 1 diabetes via recognition of a human leukocyte antigen HLA-A*0201-restricted glucose-sensitive preproinsulin peptide by the autoreactive TCR 1E6. Rigid lock-and-key binding underpinned the 1E6-HLA-A*0201-peptide interaction, whereby 1E6 docked similarly to most MHC class I-restricted TCRs. However, this interaction was extraordinarily weak because of limited contacts with MHC class I. TCR binding was highly peptide centric, dominated by two residues of the complementarity-determining region 3 (CDR3) loops that acted as an aromatic-cap over the complex of peptide and MHC class I (pMHCI). Thus, highly focused peptide-centric interactions associated with suboptimal TCR-pMHCI binding affinities might lead to thymic escape and potential CD8(+) T cell-mediated autoreactivity.

UR - http://www.nature.com/ni/journal/v13/n3/pdf/ni.2206.pdf

U2 - 10.1038/ni.2206

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VL - 13

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EP - 289

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JF - Nature Immunology

SN - 1529-2908

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