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

AUTOR(ES)

Maverakis, Emanual

FONTE

The National Academy of Sciences

RESUMO

It is not clear why the N-terminal autoantigenic determinant of myelin basic protein (MBP), Ac1–9, is dominant in the B1O.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.

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