Determinant capture by flanking golli determinant protects dominant mbp n-terminal-specific t cells from negative selection

Emanual Michael Maverakis, D. Stevens, L. Brossav, R. Mendoza, L. Macias, E. Skinner, A. Sette, A. Campaenom, E. Sercarz

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Abstract

Unlike most dominant self-determinants, why does the amino-terminal determinant on mouse MBP for the B10.PL mouse, fail to induce tolerance? One possibility was that an immediately upstream flanking region from the embryonically expressed, upstream Golli region (134 a.a.) prevented tolerance induction by outcompeting the Acl-9 amino-terminal, apparently dominant determinant for MHC access (the mechanism of "determinant capture"). Thus, we studied the 13-mer peptide, LDVMASQKRPSQR, comprised of the 4 C-terminal Golli amino acids attached to the MBP 1-9 sequence. The 13-mer is immunogenic and binds to the I-A" molecule 30 times better than Acl-9, presumably owing to a second determinant of higher binding efficiency, overlapping with 1-9. Injection of LDVMASQKRPSQR or BG2I, (a GolH-MBP product expressed in the fetal thymus including MBP residues 1-56), each fail to prime for an in vitro response to Acl-9, Ml-9 or VM1-9 suggesting that Acl-9 does not get processed from the Golli-mbp protein, or presented from the 13mer peptide. The 13-mer also fails to stimulate an Acl-9-specific Thybridoma. The data support the idea that the 13-mer is composed of a left-side dominant sequence and an overlapping, right-side recessive sequence. Support for this derived from replacing K with Y (known to increase the binding of the 1-9 component 10,000-fold) within the 13-mer. This change reversed the competition so that the right side determinant gained parity. Protection of T cells specific for Acl-9 from tolerance induction can be attributed to the better MHC-binding, left side determinant partially furnished by Golli.

Original languageEnglish (US)
JournalFASEB Journal
Volume10
Issue number6
StatePublished - 1996
Externally publishedYes

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ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

Cite this

Maverakis, E. M., Stevens, D., Brossav, L., Mendoza, R., Macias, L., Skinner, E., Sette, A., Campaenom, A., & Sercarz, E. (1996). Determinant capture by flanking golli determinant protects dominant mbp n-terminal-specific t cells from negative selection. FASEB Journal, 10(6).