Autoreactive T cells can be protected from tolerance induction through competition by flanking determinants for access to class II MHC

Emanual Michael Maverakis, Jonathan Beech, David B. Stevens, Akio Ametani, Laurent Brossay, Peter Van den Elzen, Richard Mendoza, Quoc Thai, Luis H. Macias, Doug Ethell, Celia W. Campagnoni, Anthony T. Campagnoni, Alessandro Sette, Eli E. Sercarz

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

It is not clear why the N-terminal autoantigenic determinant of myelin basic protein (MBP), Ac1-9, is dominant in the B10.PL (H-2u) mouse, given its weak I-Au-MHC binding affinity. Similarly, how do high-affinity T cells specific for this determinant avoid negative selection? Because the MBP:1-9 sequence is embryonically expressed uniquely in the context of Golli-MBP, determinants were sought within the contiguous N-terminal "Golli" region that could out-compete MBP:1-9 for MHC binding, and thereby prevent negative selection of the public response to Ac1-9, shown here to be comprised of a Vβ8.2Jβ2.7 and a Vβ8.2Jβ2.4 expansion. Specifically, we demonstrate that Ac1-9 itself can be an effective inducer of central tolerance induction; however, in the context of Golli-MBP, Ac1-9 is flanked by determinants which prevent its display to autoreactive T cells. Our data support competitive capture as a means of protecting high-affinity, autoreactive T cells from central tolerance induction.

Original languageEnglish (US)
Pages (from-to)5342-5347
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number9
DOIs
StatePublished - Apr 29 2003

ASJC Scopus subject areas

  • Genetics
  • General

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    Maverakis, E. M., Beech, J., Stevens, D. B., Ametani, A., Brossay, L., Van den Elzen, P., Mendoza, R., Thai, Q., Macias, L. H., Ethell, D., Campagnoni, C. W., Campagnoni, A. T., Sette, A., & Sercarz, E. E. (2003). Autoreactive T cells can be protected from tolerance induction through competition by flanking determinants for access to class II MHC. Proceedings of the National Academy of Sciences of the United States of America, 100(9), 5342-5347. https://doi.org/10.1073/pnas.0936151100