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Analysis of autoreactive T cells associated with murine collagen-induced arthritis using peptide-MHC multimers.

Huang, Jason C.; Vestberg, Mikael LU ; Minguela, Alfredo; Holmdahl, Rikard LU and Ward, E. Sally (2004) In International Immunology 16(2). p.283-293
Abstract
CD4+ T cells that recognize residues 256–270 of type II collagen (CII) associated with the I-Aq (Aq) molecule play a central role in disease pathogenesis in murine collagen-induced arthritis (CIA). Disease is most efficiently induced by immunization with heterologous CII, which elicits heterologous, e.g. bovine, CII256–270:I-Aq-specific T cells that only poorly cross-react with mouse CII. The self-epitope differs from heterologous CII256–270 by a conservative change of glutamic acid (heterologous) to aspartic acid (mouse) at position 266 which confers a lower affinity for binding to the I-Aq molecule. To date, characterization of the nature of T cell recognition in this model has been hindered by the lack of suitable, labeled multimeric... (More)
CD4+ T cells that recognize residues 256–270 of type II collagen (CII) associated with the I-Aq (Aq) molecule play a central role in disease pathogenesis in murine collagen-induced arthritis (CIA). Disease is most efficiently induced by immunization with heterologous CII, which elicits heterologous, e.g. bovine, CII256–270:I-Aq-specific T cells that only poorly cross-react with mouse CII. The self-epitope differs from heterologous CII256–270 by a conservative change of glutamic acid (heterologous) to aspartic acid (mouse) at position 266 which confers a lower affinity for binding to the I-Aq molecule. To date, characterization of the nature of T cell recognition in this model has been hindered by the lack of suitable, labeled multimeric peptide–MHC class II complexes. Here, we describe the biochemical properties of both recombinant bovine CII256–270:I-Aq (bCII256–270:I-Aq) and mouse CII256–270:I-Aq (mCII256–270:I-Aq) complexes, and use these as fluorescently labeled multimers (tetramers) to characterize the specificity of CII-reactive T cells. Our analyses show that an unexpectedly high percentage of bCII256–270:I-Aq-specific T cells are cross-reactive with mCII256–270:I-Aq. Interestingly, one T cell clone which has a relatively high avidity for binding to self-CII256–270:I-Aq shows a marked increase in binding avidity at physiological temperature, indicating that this TCR has unusual thermodynamic properties. Taken together, our analyses suggest that the low affinity of mCII256–270 for I-Aq may lead to a state of ignorance which can be overcome by priming CII-specific T cells with heterologous CII. This has relevance to understanding the mechanism by which CIA is induced and provides an explanation for the low arthritogenicity of mouse CII. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
T lymphocyte, rheumatoid arthritis, autoimmunity, MHC, TCR
in
International Immunology
volume
16
issue
2
pages
283 - 293
publisher
Oxford University Press
external identifiers
  • wos:000188795800011
  • pmid:14734614
  • scopus:1042280959
ISSN
1460-2377
DOI
10.1093/intimm/dxh039
language
English
LU publication?
yes
id
2d7b3c51-6bdc-4b01-add4-82580eedbbb9 (old id 120032)
date added to LUP
2007-07-13 14:03:06
date last changed
2017-01-01 04:25:07
@article{2d7b3c51-6bdc-4b01-add4-82580eedbbb9,
  abstract     = {CD4+ T cells that recognize residues 256–270 of type II collagen (CII) associated with the I-Aq (Aq) molecule play a central role in disease pathogenesis in murine collagen-induced arthritis (CIA). Disease is most efficiently induced by immunization with heterologous CII, which elicits heterologous, e.g. bovine, CII256–270:I-Aq-specific T cells that only poorly cross-react with mouse CII. The self-epitope differs from heterologous CII256–270 by a conservative change of glutamic acid (heterologous) to aspartic acid (mouse) at position 266 which confers a lower affinity for binding to the I-Aq molecule. To date, characterization of the nature of T cell recognition in this model has been hindered by the lack of suitable, labeled multimeric peptide–MHC class II complexes. Here, we describe the biochemical properties of both recombinant bovine CII256–270:I-Aq (bCII256–270:I-Aq) and mouse CII256–270:I-Aq (mCII256–270:I-Aq) complexes, and use these as fluorescently labeled multimers (tetramers) to characterize the specificity of CII-reactive T cells. Our analyses show that an unexpectedly high percentage of bCII256–270:I-Aq-specific T cells are cross-reactive with mCII256–270:I-Aq. Interestingly, one T cell clone which has a relatively high avidity for binding to self-CII256–270:I-Aq shows a marked increase in binding avidity at physiological temperature, indicating that this TCR has unusual thermodynamic properties. Taken together, our analyses suggest that the low affinity of mCII256–270 for I-Aq may lead to a state of ignorance which can be overcome by priming CII-specific T cells with heterologous CII. This has relevance to understanding the mechanism by which CIA is induced and provides an explanation for the low arthritogenicity of mouse CII.},
  author       = {Huang, Jason C. and Vestberg, Mikael and Minguela, Alfredo and Holmdahl, Rikard and Ward, E. Sally},
  issn         = {1460-2377},
  keyword      = {T lymphocyte,rheumatoid arthritis,autoimmunity,MHC,TCR},
  language     = {eng},
  number       = {2},
  pages        = {283--293},
  publisher    = {Oxford University Press},
  series       = {International Immunology},
  title        = {Analysis of autoreactive T cells associated with murine collagen-induced arthritis using peptide-MHC multimers.},
  url          = {http://dx.doi.org/10.1093/intimm/dxh039},
  volume       = {16},
  year         = {2004},
}