T cell receptor reversed polarity recognition of a self-antigen major histocompatibility complex

Dennis X Beringer, Fleur S Kleijwegt, Florian Wiede, Arno R Van Der Slik, Kylie K L Loh, Jan Petersen, Nadine L Dudek, Gaby Duinkerken, Sandra Laban, Antoinette M Joosten, Julian P Vivian, Zhenjun Chen, Adam P Uldrich, Dale I Godfrey, James McCluskey, David A Price, Kristen J Radford, Anthony W Purcell, Tatjana Nikolic, Hugh H Reid & 3 others Tony Tiganis, Bart O Roep, Jamie Rossjohn

Research output: Contribution to journalArticleResearchpeer-review

63 Citations (Scopus)

Abstract

Central to adaptive immunity is the interaction between the alphabeta T cell receptor (TCR) and peptide presented by the major histocompatibility complex (MHC) molecule. Presumably reflecting TCR-MHC bias and T cell signaling constraints, the TCR universally adopts a canonical polarity atop the MHC. We report the structures of two TCRs, derived from human induced T regulatory (iTreg) cells, complexed to an MHC class II molecule presenting a proinsulin-derived peptide. The ternary complexes revealed a 180 degrees polarity reversal compared to all other TCR-peptide-MHC complex structures. Namely, the iTreg TCR alpha-chain and beta-chain are overlaid with the alpha-chain and beta-chain of MHC class II, respectively. Nevertheless, this TCR interaction elicited a peptide-reactive, MHC-restricted T cell signal. Thus TCRs are not hardwired to interact with MHC molecules in a stereotypic manner to elicit a T cell signal, a finding that fundamentally challenges our understanding of TCR recognition.
Original languageEnglish
Pages (from-to)1153 - 1161
Number of pages9
JournalNature Immunology
Volume16
Issue number11
DOIs
Publication statusPublished - 2015

Cite this

Beringer, Dennis X ; Kleijwegt, Fleur S ; Wiede, Florian ; Van Der Slik, Arno R ; Loh, Kylie K L ; Petersen, Jan ; Dudek, Nadine L ; Duinkerken, Gaby ; Laban, Sandra ; Joosten, Antoinette M ; Vivian, Julian P ; Chen, Zhenjun ; Uldrich, Adam P ; Godfrey, Dale I ; McCluskey, James ; Price, David A ; Radford, Kristen J ; Purcell, Anthony W ; Nikolic, Tatjana ; Reid, Hugh H ; Tiganis, Tony ; Roep, Bart O ; Rossjohn, Jamie. / T cell receptor reversed polarity recognition of a self-antigen major histocompatibility complex. In: Nature Immunology. 2015 ; Vol. 16, No. 11. pp. 1153 - 1161.
@article{1f04c9a2994d4affbca6c511c41e155c,
title = "T cell receptor reversed polarity recognition of a self-antigen major histocompatibility complex",
abstract = "Central to adaptive immunity is the interaction between the alphabeta T cell receptor (TCR) and peptide presented by the major histocompatibility complex (MHC) molecule. Presumably reflecting TCR-MHC bias and T cell signaling constraints, the TCR universally adopts a canonical polarity atop the MHC. We report the structures of two TCRs, derived from human induced T regulatory (iTreg) cells, complexed to an MHC class II molecule presenting a proinsulin-derived peptide. The ternary complexes revealed a 180 degrees polarity reversal compared to all other TCR-peptide-MHC complex structures. Namely, the iTreg TCR alpha-chain and beta-chain are overlaid with the alpha-chain and beta-chain of MHC class II, respectively. Nevertheless, this TCR interaction elicited a peptide-reactive, MHC-restricted T cell signal. Thus TCRs are not hardwired to interact with MHC molecules in a stereotypic manner to elicit a T cell signal, a finding that fundamentally challenges our understanding of TCR recognition.",
author = "Beringer, {Dennis X} and Kleijwegt, {Fleur S} and Florian Wiede and {Van Der Slik}, {Arno R} and Loh, {Kylie K L} and Jan Petersen and Dudek, {Nadine L} and Gaby Duinkerken and Sandra Laban and Joosten, {Antoinette M} and Vivian, {Julian P} and Zhenjun Chen and Uldrich, {Adam P} and Godfrey, {Dale I} and James McCluskey and Price, {David A} and Radford, {Kristen J} and Purcell, {Anthony W} and Tatjana Nikolic and Reid, {Hugh H} and Tony Tiganis and Roep, {Bart O} and Jamie Rossjohn",
year = "2015",
doi = "10.1038/ni.3271",
language = "English",
volume = "16",
pages = "1153 -- 1161",
journal = "Nature Immunology",
issn = "1529-2908",
publisher = "Nature Publishing Group",
number = "11",

}

Beringer, DX, Kleijwegt, FS, Wiede, F, Van Der Slik, AR, Loh, KKL, Petersen, J, Dudek, NL, Duinkerken, G, Laban, S, Joosten, AM, Vivian, JP, Chen, Z, Uldrich, AP, Godfrey, DI, McCluskey, J, Price, DA, Radford, KJ, Purcell, AW, Nikolic, T, Reid, HH, Tiganis, T, Roep, BO & Rossjohn, J 2015, 'T cell receptor reversed polarity recognition of a self-antigen major histocompatibility complex', Nature Immunology, vol. 16, no. 11, pp. 1153 - 1161. https://doi.org/10.1038/ni.3271

T cell receptor reversed polarity recognition of a self-antigen major histocompatibility complex. / Beringer, Dennis X; Kleijwegt, Fleur S; Wiede, Florian; Van Der Slik, Arno R; Loh, Kylie K L; Petersen, Jan; Dudek, Nadine L; Duinkerken, Gaby; Laban, Sandra; Joosten, Antoinette M; Vivian, Julian P; Chen, Zhenjun; Uldrich, Adam P; Godfrey, Dale I; McCluskey, James; Price, David A; Radford, Kristen J; Purcell, Anthony W; Nikolic, Tatjana; Reid, Hugh H; Tiganis, Tony; Roep, Bart O; Rossjohn, Jamie.

In: Nature Immunology, Vol. 16, No. 11, 2015, p. 1153 - 1161.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - T cell receptor reversed polarity recognition of a self-antigen major histocompatibility complex

AU - Beringer, Dennis X

AU - Kleijwegt, Fleur S

AU - Wiede, Florian

AU - Van Der Slik, Arno R

AU - Loh, Kylie K L

AU - Petersen, Jan

AU - Dudek, Nadine L

AU - Duinkerken, Gaby

AU - Laban, Sandra

AU - Joosten, Antoinette M

AU - Vivian, Julian P

AU - Chen, Zhenjun

AU - Uldrich, Adam P

AU - Godfrey, Dale I

AU - McCluskey, James

AU - Price, David A

AU - Radford, Kristen J

AU - Purcell, Anthony W

AU - Nikolic, Tatjana

AU - Reid, Hugh H

AU - Tiganis, Tony

AU - Roep, Bart O

AU - Rossjohn, Jamie

PY - 2015

Y1 - 2015

N2 - Central to adaptive immunity is the interaction between the alphabeta T cell receptor (TCR) and peptide presented by the major histocompatibility complex (MHC) molecule. Presumably reflecting TCR-MHC bias and T cell signaling constraints, the TCR universally adopts a canonical polarity atop the MHC. We report the structures of two TCRs, derived from human induced T regulatory (iTreg) cells, complexed to an MHC class II molecule presenting a proinsulin-derived peptide. The ternary complexes revealed a 180 degrees polarity reversal compared to all other TCR-peptide-MHC complex structures. Namely, the iTreg TCR alpha-chain and beta-chain are overlaid with the alpha-chain and beta-chain of MHC class II, respectively. Nevertheless, this TCR interaction elicited a peptide-reactive, MHC-restricted T cell signal. Thus TCRs are not hardwired to interact with MHC molecules in a stereotypic manner to elicit a T cell signal, a finding that fundamentally challenges our understanding of TCR recognition.

AB - Central to adaptive immunity is the interaction between the alphabeta T cell receptor (TCR) and peptide presented by the major histocompatibility complex (MHC) molecule. Presumably reflecting TCR-MHC bias and T cell signaling constraints, the TCR universally adopts a canonical polarity atop the MHC. We report the structures of two TCRs, derived from human induced T regulatory (iTreg) cells, complexed to an MHC class II molecule presenting a proinsulin-derived peptide. The ternary complexes revealed a 180 degrees polarity reversal compared to all other TCR-peptide-MHC complex structures. Namely, the iTreg TCR alpha-chain and beta-chain are overlaid with the alpha-chain and beta-chain of MHC class II, respectively. Nevertheless, this TCR interaction elicited a peptide-reactive, MHC-restricted T cell signal. Thus TCRs are not hardwired to interact with MHC molecules in a stereotypic manner to elicit a T cell signal, a finding that fundamentally challenges our understanding of TCR recognition.

UR - http://dx.doi.org/10.1038/ni.3271

U2 - 10.1038/ni.3271

DO - 10.1038/ni.3271

M3 - Article

VL - 16

SP - 1153

EP - 1161

JO - Nature Immunology

JF - Nature Immunology

SN - 1529-2908

IS - 11

ER -