Canonical T cell receptor docking on peptide–MHC is essential for T cell signaling

Pirooz Zareie; Christopher Szeto; Carine Farenc; Sachith D. Gunasinghe; Elizabeth M. Kolawole; Angela Nguyen; Chantelle Blyth; Xavier Y.X. Sng; Jasmine Li; Claerwen M. Jones; Alex J. Fulcher; Jesica R. Jacobs; Qianru Wei; Lukasz Wojciech; Jan Petersen; Nicholas R.J. Gascoigne; Brian D. Evavold; Katharina Gaus; Stephanie Gras; Jamie Rossjohn; Nicole L. la Gruta

doi:10.1126/science.abe9124

Canonical T cell receptor docking on peptide–MHC is essential for T cell signaling

Pirooz Zareie, Christopher Szeto, Carine Farenc, Sachith D. Gunasinghe, Elizabeth M. Kolawole, Angela Nguyen, Chantelle Blyth, Xavier Y.X. Sng, Jasmine Li, Claerwen M. Jones, Alex J. Fulcher, Jesica R. Jacobs, Qianru Wei, Lukasz Wojciech, Jan Petersen, Nicholas R.J. Gascoigne, Brian D. Evavold, Katharina Gaus, Stephanie Gras, Jamie RossjohnNicole L. la Gruta

Research output: Contribution to journal › Article › Research › peer-review

77 Citations (Scopus)

Abstract

T cell receptor (TCR) recognition of peptide–major histocompatibility complexes (pMHCs) is characterized by a highly conserved docking polarity. Whether this polarity is driven by recognition or signaling constraints remains unclear. Using “reversed-docking” TCRb-variable (TRBV) 17⁺ TCRs from the naïve mouse CD8⁺ T cell repertoire that recognizes the H-2D^b–NP₃₆₆ epitope, we demonstrate that their inability to support T cell activation and in vivo recruitment is a direct consequence of reversed docking polarity and not TCR–pMHCI binding or clustering characteristics. Canonical TCR–pMHCI docking optimally localizes CD8/Lck to the CD3 complex, which is prevented by reversed TCR–pMHCI polarity. The requirement for canonical docking was circumvented by dissociating Lck from CD8. Thus, the consensus TCR–pMHC docking topology is mandated by T cell signaling constraints.

Original language	English
Article number	eabe9124
Number of pages	14
Journal	Science
Volume	372
Issue number	6546
DOIs	https://doi.org/10.1126/science.abe9124
Publication status	Published - 4 Jun 2021

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10.1126/science.abe9124

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Zareie, P., Szeto, C., Farenc, C., Gunasinghe, S. D., Kolawole, E. M., Nguyen, A., Blyth, C., Sng, X. Y. X., Li, J., Jones, C. M., Fulcher, A. J., Jacobs, J. R., Wei, Q., Wojciech, L., Petersen, J., Gascoigne, N. R. J., Evavold, B. D., Gaus, K., Gras, S., ... la Gruta, N. L. (2021). Canonical T cell receptor docking on peptide–MHC is essential for T cell signaling. Science, 372(6546), Article eabe9124. https://doi.org/10.1126/science.abe9124

@article{a2c20e61bf6342ee9cb75bd0b583ed80,

title = "Canonical T cell receptor docking on peptide–MHC is essential for T cell signaling",

abstract = "T cell receptor (TCR) recognition of peptide–major histocompatibility complexes (pMHCs) is characterized by a highly conserved docking polarity. Whether this polarity is driven by recognition or signaling constraints remains unclear. Using “reversed-docking” TCRb-variable (TRBV) 17+ TCRs from the na{\"i}ve mouse CD8+ T cell repertoire that recognizes the H-2Db–NP366 epitope, we demonstrate that their inability to support T cell activation and in vivo recruitment is a direct consequence of reversed docking polarity and not TCR–pMHCI binding or clustering characteristics. Canonical TCR–pMHCI docking optimally localizes CD8/Lck to the CD3 complex, which is prevented by reversed TCR–pMHCI polarity. The requirement for canonical docking was circumvented by dissociating Lck from CD8. Thus, the consensus TCR–pMHC docking topology is mandated by T cell signaling constraints.",

author = "Pirooz Zareie and Christopher Szeto and Carine Farenc and Gunasinghe, \{Sachith D.\} and Kolawole, \{Elizabeth M.\} and Angela Nguyen and Chantelle Blyth and Sng, \{Xavier Y.X.\} and Jasmine Li and Jones, \{Claerwen M.\} and Fulcher, \{Alex J.\} and Jacobs, \{Jesica R.\} and Qianru Wei and Lukasz Wojciech and Jan Petersen and Gascoigne, \{Nicholas R.J.\} and Evavold, \{Brian D.\} and Katharina Gaus and Stephanie Gras and Jamie Rossjohn and \{la Gruta\}, \{Nicole L.\}",

year = "2021",

month = jun,

day = "4",

doi = "10.1126/science.abe9124",

language = "English",

volume = "372",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science (AAAS)",

number = "6546",

}

Zareie, P, Szeto, C, Farenc, C, Gunasinghe, SD, Kolawole, EM, Nguyen, A, Blyth, C, Sng, XYX, Li, J, Jones, CM, Fulcher, AJ, Jacobs, JR, Wei, Q, Wojciech, L, Petersen, J, Gascoigne, NRJ, Evavold, BD, Gaus, K, Gras, S , Rossjohn, J & la Gruta, NL 2021, 'Canonical T cell receptor docking on peptide–MHC is essential for T cell signaling', Science, vol. 372, no. 6546, eabe9124. https://doi.org/10.1126/science.abe9124

TY - JOUR

T1 - Canonical T cell receptor docking on peptide–MHC is essential for T cell signaling

AU - Zareie, Pirooz

AU - Szeto, Christopher

AU - Farenc, Carine

AU - Gunasinghe, Sachith D.

AU - Kolawole, Elizabeth M.

AU - Nguyen, Angela

AU - Blyth, Chantelle

AU - Sng, Xavier Y.X.

AU - Li, Jasmine

AU - Jones, Claerwen M.

AU - Fulcher, Alex J.

AU - Jacobs, Jesica R.

AU - Wei, Qianru

AU - Wojciech, Lukasz

AU - Petersen, Jan

AU - Gascoigne, Nicholas R.J.

AU - Evavold, Brian D.

AU - Gaus, Katharina

AU - Gras, Stephanie

AU - Rossjohn, Jamie

AU - la Gruta, Nicole L.

PY - 2021/6/4

Y1 - 2021/6/4

N2 - T cell receptor (TCR) recognition of peptide–major histocompatibility complexes (pMHCs) is characterized by a highly conserved docking polarity. Whether this polarity is driven by recognition or signaling constraints remains unclear. Using “reversed-docking” TCRb-variable (TRBV) 17+ TCRs from the naïve mouse CD8+ T cell repertoire that recognizes the H-2Db–NP366 epitope, we demonstrate that their inability to support T cell activation and in vivo recruitment is a direct consequence of reversed docking polarity and not TCR–pMHCI binding or clustering characteristics. Canonical TCR–pMHCI docking optimally localizes CD8/Lck to the CD3 complex, which is prevented by reversed TCR–pMHCI polarity. The requirement for canonical docking was circumvented by dissociating Lck from CD8. Thus, the consensus TCR–pMHC docking topology is mandated by T cell signaling constraints.

AB - T cell receptor (TCR) recognition of peptide–major histocompatibility complexes (pMHCs) is characterized by a highly conserved docking polarity. Whether this polarity is driven by recognition or signaling constraints remains unclear. Using “reversed-docking” TCRb-variable (TRBV) 17+ TCRs from the naïve mouse CD8+ T cell repertoire that recognizes the H-2Db–NP366 epitope, we demonstrate that their inability to support T cell activation and in vivo recruitment is a direct consequence of reversed docking polarity and not TCR–pMHCI binding or clustering characteristics. Canonical TCR–pMHCI docking optimally localizes CD8/Lck to the CD3 complex, which is prevented by reversed TCR–pMHCI polarity. The requirement for canonical docking was circumvented by dissociating Lck from CD8. Thus, the consensus TCR–pMHC docking topology is mandated by T cell signaling constraints.

UR - https://www.scopus.com/pages/publications/85107613957

U2 - 10.1126/science.abe9124

DO - 10.1126/science.abe9124

M3 - Article

C2 - 34083463

AN - SCOPUS:85107613957

SN - 0036-8075

VL - 372

JO - Science

JF - Science

IS - 6546

M1 - eabe9124

ER -

Canonical T cell receptor docking on peptide–MHC is essential for T cell signaling

Abstract

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Other files and links

Accompanying artwork for media release: Monash researchers make fundamental advance in understanding T cell immunity

Dissecting the requirements for effective T cell activation

ARC Centre of Excellence in Advanced Molecular Imaging

Cite this

Canonical T cell receptor docking on peptide–MHC is essential for T cell signaling

Abstract

Access to Document

Other files and links

Research output

Accompanying artwork for media release: Monash researchers make fundamental advance in understanding T cell immunity

Projects

Dissecting the requirements for effective T cell activation

ARC Centre of Excellence in Advanced Molecular Imaging

Cite this