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Hard wiring of T cell receptor specificity for the major histocompatibility complex is underpinned by ICR adaptability.

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Title: Hard wiring of T cell receptor specificity for the major histocompatibility complex is underpinned by ICR adaptability.
Authors: Burrows, Scott R.1, Zhenjun Chen2, Archbold, Julia K.3, Tynan, Fleur E.3, Beddoe, Travis3, Kjer-Nielsen, Lars2, Miles, John J.1, Khanna, Rajiv1, Moss, Denis J.1, Yu Chih Liu3, Gras, Stephanie3, Kostenko, Lyudmila2, Brennan, Rebekah M.1, Clements, Craig S.3, Brooks, Andrew G.2, Purcell, Anthony W.4, McCluskey, James2 jamesm1@unimeIb.edu.au, Rossjohn, Jamie3 jamie.rossjohn@med.monash.edu.au
Source: Proceedings of the National Academy of Sciences of the United States of America. 6/8/2010, Vol. 107 Issue 23, p10608-10613. 6p.
Subjects: T cell receptors, Antigens, Major histocompatibility complex, Molecules, Genetic mutation
Abstract: αβ 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-l structural database shows that the nongermline-encoded complementaritydetermining region (CDR)-3 loops often contact the MHC-l, and the germline-encoded CDR1 and -2 loops frequently participate in peptide-mediated interactions. Nevertheless, different TCR5 adopt a roughly conserved docking mode over the pMHC-l, 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 pHLAB*35O8. 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-l 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. [ABSTRACT FROM AUTHOR]
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Database: Engineering Source
Description
Abstract:αβ 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-l structural database shows that the nongermline-encoded complementaritydetermining region (CDR)-3 loops often contact the MHC-l, and the germline-encoded CDR1 and -2 loops frequently participate in peptide-mediated interactions. Nevertheless, different TCR5 adopt a roughly conserved docking mode over the pMHC-l, 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 pHLAB*35O8. 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-l 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. [ABSTRACT FROM AUTHOR]
ISSN:00278424
DOI:10.1073/pnas.1004926107