title: Autoreactive T cells can be protected from tolerance induction through competition by flanking determinants for access to class II MHC.
abstract: It is not clear why the N-terminal autoantigenic determinant of myelin basic protein (MBP), Ac1-9, is dominant in the B1O.PL (H-2(u)) mouse, given its weak I-A(u)-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 V beta 8.2J beta 2.7 and a V beta 8.2J beta 2.4 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.
authors.affiliation: La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Emanual
authors.initials: E
authors.lastname: Maverakis
authors.forename: Jonathan
authors.initials: J
authors.lastname: Beech
authors.forename: David B
authors.initials: DB
authors.lastname: Stevens
authors.forename: Akio
authors.initials: A
authors.lastname: Ametani
authors.forename: Laurent
authors.initials: L
authors.lastname: Brossay
authors.forename: Peter
authors.initials: P
authors.lastname: van den Elzen
authors.forename: Richard
authors.initials: R
authors.lastname: Mendoza
authors.forename: Quoc
authors.initials: Q
authors.lastname: Thai
authors.forename: Luis H
authors.initials: LH
authors.lastname: Macias
authors.forename: Doug
authors.initials: D
authors.lastname: Ethell
authors.forename: Celia W
authors.initials: CW
authors.lastname: Campagnoni
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Campagnoni
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.forename: Eli E
authors.initials: EE
authors.lastname: Sercarz
mesh_terms: D000818:Animals; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D007108:Immune Tolerance; D051379:Mice; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000949:Histocompatibility Antigens Class II