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Title: Hard wiring of T cell receptor specificity for the major histocompatibility complex is underpinned by TCR adaptability

Abstract

{alpha}{beta} T cell receptors (TCRs) are genetically restricted to corecognize peptide antigens bound to self-major histocompatibility complex (pMHC) molecules; however, the basis for this MHC specificity remains unclear. Despite the current dogma, evaluation of the TCR-pMHC-I structural database shows that the nongermline-encoded complementarity-determining region (CDR)-3 loops often contact the MHC-I, and the germline-encoded CDR1 and -2 loops frequently participate in peptide-mediated interactions. Nevertheless, different TCRs adopt a roughly conserved docking mode over the pMHC-I, in which three MHC-I residues (65, 69, and 155) are invariably contacted by the TCR in one way or another. Nonetheless, the impact of mutations at these three positions, either individually or together, was not uniformly detrimental to TCR recognition of pHLA-B*0801 or pHLA-B*3508. Moreover, when TCR-pMHC-I recognition was impaired, this could be partially restored by expression of the CD8 coreceptor. The structure of a TCR-pMHC-I complex in which these three (65, 69, and 155) MHC-I positions were all mutated resulted in shifting of the TCR footprint relative to the cognate complex and formation of compensatory interactions. Collectively, our findings reveal the inherent adaptability of the TCR in maintaining peptide recognition while accommodating changes to the central docking site on the pMHC-I.

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;  [1]
  1. Monash
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE
OSTI Identifier:
1002497
Resource Type:
Journal Article
Journal Name:
Proc. Natl. Acad. Sci. USA
Additional Journal Information:
Journal Volume: 107; Journal Issue: (23) ; 06, 2010; Journal ID: ISSN 0027-8424
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; ANTIGENS; EVALUATION; HISTOCOMPATIBILITY COMPLEX; MUTATIONS; PEPTIDES; RESIDUES; SPECIFICITY

Citation Formats

Burrows, Scott R, Chen, Zhenjun, Archbold, Julia K, Tynan, Fleur E, Beddoe, Travis, Kjer-Nielsen, Lars, Miles, John J, Khanna, Rajiv, Moss, Denis J, Liu, Yu Chih, Gras, Stephanie, Kostenko, Lyudmila, Brennan, Rebekah M, Clements, Craig S, Brooks, Andrew G, Purcell, Anthony W, McCluskey, James, Rossjohn, Jamie, Queensland Inst. of Med. Rsrch.), and Melbourne). Hard wiring of T cell receptor specificity for the major histocompatibility complex is underpinned by TCR adaptability. United States: N. p., 2010. Web. doi:10.1073/pnas.1004926107.
Burrows, Scott R, Chen, Zhenjun, Archbold, Julia K, Tynan, Fleur E, Beddoe, Travis, Kjer-Nielsen, Lars, Miles, John J, Khanna, Rajiv, Moss, Denis J, Liu, Yu Chih, Gras, Stephanie, Kostenko, Lyudmila, Brennan, Rebekah M, Clements, Craig S, Brooks, Andrew G, Purcell, Anthony W, McCluskey, James, Rossjohn, Jamie, Queensland Inst. of Med. Rsrch.), & Melbourne). Hard wiring of T cell receptor specificity for the major histocompatibility complex is underpinned by TCR adaptability. United States. https://doi.org/10.1073/pnas.1004926107
Burrows, Scott R, Chen, Zhenjun, Archbold, Julia K, Tynan, Fleur E, Beddoe, Travis, Kjer-Nielsen, Lars, Miles, John J, Khanna, Rajiv, Moss, Denis J, Liu, Yu Chih, Gras, Stephanie, Kostenko, Lyudmila, Brennan, Rebekah M, Clements, Craig S, Brooks, Andrew G, Purcell, Anthony W, McCluskey, James, Rossjohn, Jamie, Queensland Inst. of Med. Rsrch.), and Melbourne). 2010. "Hard wiring of T cell receptor specificity for the major histocompatibility complex is underpinned by TCR adaptability". United States. https://doi.org/10.1073/pnas.1004926107.
@article{osti_1002497,
title = {Hard wiring of T cell receptor specificity for the major histocompatibility complex is underpinned by TCR adaptability},
author = {Burrows, Scott R and Chen, Zhenjun and Archbold, Julia K and Tynan, Fleur E and Beddoe, Travis and Kjer-Nielsen, Lars and Miles, John J and Khanna, Rajiv and Moss, Denis J and Liu, Yu Chih and Gras, Stephanie and Kostenko, Lyudmila and Brennan, Rebekah M and Clements, Craig S and Brooks, Andrew G and Purcell, Anthony W and McCluskey, James and Rossjohn, Jamie and Queensland Inst. of Med. Rsrch.) and Melbourne)},
abstractNote = {{alpha}{beta} T cell receptors (TCRs) are genetically restricted to corecognize peptide antigens bound to self-major histocompatibility complex (pMHC) molecules; however, the basis for this MHC specificity remains unclear. Despite the current dogma, evaluation of the TCR-pMHC-I structural database shows that the nongermline-encoded complementarity-determining region (CDR)-3 loops often contact the MHC-I, and the germline-encoded CDR1 and -2 loops frequently participate in peptide-mediated interactions. Nevertheless, different TCRs adopt a roughly conserved docking mode over the pMHC-I, in which three MHC-I residues (65, 69, and 155) are invariably contacted by the TCR in one way or another. Nonetheless, the impact of mutations at these three positions, either individually or together, was not uniformly detrimental to TCR recognition of pHLA-B*0801 or pHLA-B*3508. Moreover, when TCR-pMHC-I recognition was impaired, this could be partially restored by expression of the CD8 coreceptor. The structure of a TCR-pMHC-I complex in which these three (65, 69, and 155) MHC-I positions were all mutated resulted in shifting of the TCR footprint relative to the cognate complex and formation of compensatory interactions. Collectively, our findings reveal the inherent adaptability of the TCR in maintaining peptide recognition while accommodating changes to the central docking site on the pMHC-I.},
doi = {10.1073/pnas.1004926107},
url = {https://www.osti.gov/biblio/1002497}, journal = {Proc. Natl. Acad. Sci. USA},
issn = {0027-8424},
number = (23) ; 06, 2010,
volume = 107,
place = {United States},
year = {Wed Jul 07 00:00:00 EDT 2010},
month = {Wed Jul 07 00:00:00 EDT 2010}
}