Autoreactive T cells can be protected from tolerance induction through competition by flanking determinants for access to class II MHC.
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.
Maverakis
Emanual
E
La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, CA 92121, USA.
Beech
Jonathan
J
Stevens
David B
DB
Ametani
Akio
A
Brossay
Laurent
L
van den Elzen
Peter
P
Mendoza
Richard
R
Thai
Quoc
Q
Macias
Luis H
LH
Ethell
Doug
D
Campagnoni
Celia W
CW
Campagnoni
Anthony T
AT
Sette
Alessandro
A
Sercarz
Eli E
EE
D000818:Animals; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D007108:Immune Tolerance; D051379:Mice; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000276:immunology*
D000949:Histocompatibility Antigens Class II