CD8 coreceptor-mediated focusing can reorder the agonist hierarchy of peptide ligands recognized via the T cell receptor

Mathew Clement; Lea Knezevic; Tamsin Dockree; James E McLaren; Kristin Ladell; Kelly L Miners; Sian Llewellyn-Lacey; Anzelika Rubina; Ore Francis; David K Cole; Andrew K Sewell; John S Bridgeman; David A Price; Hugo A van den Berg; Linda Wooldridge

doi:10.1073/pnas.2019639118

CD8 coreceptor-mediated focusing can reorder the agonist hierarchy of peptide ligands recognized via the T cell receptor

Mathew Clement, Lea Knezevic, Tamsin Dockree, James E McLaren, Kristin Ladell, Kelly L Miners, Sian Llewellyn-Lacey, Anzelika Rubina, Ore Francis, David K Cole, Andrew K Sewell, John S Bridgeman, David A Price, Hugo A van den Berg, Linda Wooldridge^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

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Abstract

CD8+ T cells are inherently cross-reactive and recognize numerous peptide antigens in the context of a given major histocompatibility complex class I (MHCI) molecule via the clonotypically expressed T cell receptor (TCR). The lineally expressed coreceptor CD8 interacts coordinately with MHCI at a distinct and largely invariant site to slow the TCR/peptide-MHCI (pMHCI) dissociation rate and enhance antigen sensitivity. However, this biological effect is not necessarily uniform, and theoretical models suggest that antigen sensitivity can be modulated in a differential manner by CD8. We used two intrinsically controlled systems to determine how the relationship between the TCR/pMHCI interaction and the pMHCI/CD8 interaction affects the functional sensitivity of antigen recognition. Our data show that modulation of the pMHCI/CD8 interaction can reorder the agonist hierarchy of peptide ligands across a spectrum of affinities for the TCR.

Original language	English
Article number	e2019639118
Number of pages	5
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	118
Issue number	29
DOIs	https://doi.org/10.1073/pnas.2019639118
Publication status	Published - 20 Jul 2021

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS. We thank Andrew Herman and Lorena Sueiro Ballesteros for assistance with cell sorting at the University of Bristol Flow Cytometry Facility. This work was funded by the Wellcome Trust (Grants WT079848MA and WT099067AIA). Additional support was received from the Horizon 2020 Research and Innovation Programme of the European Union via Marie Sklodowska-Curie Grant Agreement 721358 and from the Biotechnology and Biological Sciences Research Council (Grant BB/H001085/ 1). A.K.S. and D.A.P. were supported by Wellcome Trust Senior Investigator Awards.

Publisher Copyright:
© 2021 National Academy of Sciences. All rights reserved.

Keywords

CD8 coreceptor
pMHCI
T cell activation

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Clement, M., Knezevic, L., Dockree, T., McLaren, J. E., Ladell, K., Miners, K. L., Llewellyn-Lacey, S., Rubina, A., Francis, O., Cole, D. K., Sewell, A. K., Bridgeman, J. S., Price, D. A., van den Berg, H. A., & Wooldridge, L. (2021). CD8 coreceptor-mediated focusing can reorder the agonist hierarchy of peptide ligands recognized via the T cell receptor. Proceedings of the National Academy of Sciences of the United States of America, 118(29), Article e2019639118. https://doi.org/10.1073/pnas.2019639118

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title = "CD8 coreceptor-mediated focusing can reorder the agonist hierarchy of peptide ligands recognized via the T cell receptor",

abstract = "CD8+ T cells are inherently cross-reactive and recognize numerous peptide antigens in the context of a given major histocompatibility complex class I (MHCI) molecule via the clonotypically expressed T cell receptor (TCR). The lineally expressed coreceptor CD8 interacts coordinately with MHCI at a distinct and largely invariant site to slow the TCR/peptide-MHCI (pMHCI) dissociation rate and enhance antigen sensitivity. However, this biological effect is not necessarily uniform, and theoretical models suggest that antigen sensitivity can be modulated in a differential manner by CD8. We used two intrinsically controlled systems to determine how the relationship between the TCR/pMHCI interaction and the pMHCI/CD8 interaction affects the functional sensitivity of antigen recognition. Our data show that modulation of the pMHCI/CD8 interaction can reorder the agonist hierarchy of peptide ligands across a spectrum of affinities for the TCR.",

keywords = "CD8 coreceptor, pMHCI, T cell activation",

author = "Mathew Clement and Lea Knezevic and Tamsin Dockree and McLaren, {James E} and Kristin Ladell and Miners, {Kelly L} and Sian Llewellyn-Lacey and Anzelika Rubina and Ore Francis and Cole, {David K} and Sewell, {Andrew K} and Bridgeman, {John S} and Price, {David A} and {van den Berg}, {Hugo A} and Linda Wooldridge",

note = "Funding Information: ACKNOWLEDGMENTS. We thank Andrew Herman and Lorena Sueiro Ballesteros for assistance with cell sorting at the University of Bristol Flow Cytometry Facility. This work was funded by the Wellcome Trust (Grants WT079848MA and WT099067AIA). Additional support was received from the Horizon 2020 Research and Innovation Programme of the European Union via Marie Sklodowska-Curie Grant Agreement 721358 and from the Biotechnology and Biological Sciences Research Council (Grant BB/H001085/ 1). A.K.S. and D.A.P. were supported by Wellcome Trust Senior Investigator Awards. Publisher Copyright: {\textcopyright} 2021 National Academy of Sciences. All rights reserved.",

year = "2021",

month = jul,

day = "20",

doi = "10.1073/pnas.2019639118",

language = "English",

volume = "118",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

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Clement, M, Knezevic, L, Dockree, T, McLaren, JE, Ladell, K, Miners, KL, Llewellyn-Lacey, S, Rubina, A, Francis, O, Cole, DK, Sewell, AK, Bridgeman, JS, Price, DA, van den Berg, HA & Wooldridge, L 2021, 'CD8 coreceptor-mediated focusing can reorder the agonist hierarchy of peptide ligands recognized via the T cell receptor', Proceedings of the National Academy of Sciences of the United States of America, vol. 118, no. 29, e2019639118. https://doi.org/10.1073/pnas.2019639118

CD8 coreceptor-mediated focusing can reorder the agonist hierarchy of peptide ligands recognized via the T cell receptor. / Clement, Mathew; Knezevic, Lea; Dockree, Tamsin et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 118, No. 29, e2019639118, 20.07.2021.

Research output: Contribution to journal › Article (Academic Journal) › peer-review

TY - JOUR

T1 - CD8 coreceptor-mediated focusing can reorder the agonist hierarchy of peptide ligands recognized via the T cell receptor

AU - Clement, Mathew

AU - Knezevic, Lea

AU - Dockree, Tamsin

AU - McLaren, James E

AU - Ladell, Kristin

AU - Miners, Kelly L

AU - Llewellyn-Lacey, Sian

AU - Rubina, Anzelika

AU - Francis, Ore

AU - Cole, David K

AU - Sewell, Andrew K

AU - Bridgeman, John S

AU - Price, David A

AU - van den Berg, Hugo A

AU - Wooldridge, Linda

N1 - Funding Information: ACKNOWLEDGMENTS. We thank Andrew Herman and Lorena Sueiro Ballesteros for assistance with cell sorting at the University of Bristol Flow Cytometry Facility. This work was funded by the Wellcome Trust (Grants WT079848MA and WT099067AIA). Additional support was received from the Horizon 2020 Research and Innovation Programme of the European Union via Marie Sklodowska-Curie Grant Agreement 721358 and from the Biotechnology and Biological Sciences Research Council (Grant BB/H001085/ 1). A.K.S. and D.A.P. were supported by Wellcome Trust Senior Investigator Awards. Publisher Copyright: © 2021 National Academy of Sciences. All rights reserved.

PY - 2021/7/20

Y1 - 2021/7/20

N2 - CD8+ T cells are inherently cross-reactive and recognize numerous peptide antigens in the context of a given major histocompatibility complex class I (MHCI) molecule via the clonotypically expressed T cell receptor (TCR). The lineally expressed coreceptor CD8 interacts coordinately with MHCI at a distinct and largely invariant site to slow the TCR/peptide-MHCI (pMHCI) dissociation rate and enhance antigen sensitivity. However, this biological effect is not necessarily uniform, and theoretical models suggest that antigen sensitivity can be modulated in a differential manner by CD8. We used two intrinsically controlled systems to determine how the relationship between the TCR/pMHCI interaction and the pMHCI/CD8 interaction affects the functional sensitivity of antigen recognition. Our data show that modulation of the pMHCI/CD8 interaction can reorder the agonist hierarchy of peptide ligands across a spectrum of affinities for the TCR.

AB - CD8+ T cells are inherently cross-reactive and recognize numerous peptide antigens in the context of a given major histocompatibility complex class I (MHCI) molecule via the clonotypically expressed T cell receptor (TCR). The lineally expressed coreceptor CD8 interacts coordinately with MHCI at a distinct and largely invariant site to slow the TCR/peptide-MHCI (pMHCI) dissociation rate and enhance antigen sensitivity. However, this biological effect is not necessarily uniform, and theoretical models suggest that antigen sensitivity can be modulated in a differential manner by CD8. We used two intrinsically controlled systems to determine how the relationship between the TCR/pMHCI interaction and the pMHCI/CD8 interaction affects the functional sensitivity of antigen recognition. Our data show that modulation of the pMHCI/CD8 interaction can reorder the agonist hierarchy of peptide ligands across a spectrum of affinities for the TCR.

KW - CD8 coreceptor

KW - pMHCI

KW - T cell activation

U2 - 10.1073/pnas.2019639118

DO - 10.1073/pnas.2019639118

M3 - Article (Academic Journal)

C2 - 34272276

SN - 0027-8424

VL - 118

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 29

M1 - e2019639118

ER -

CD8 coreceptor-mediated focusing can reorder the agonist hierarchy of peptide ligands recognized via the T cell receptor

Abstract

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