GENETIC-BASIS FOR T-CELL RECOGNITION OF A MAJOR HISTOCOMPATIBILITY COMPLEX CLASS II-RESTRICTED NEO-SELF PEPTIDE

We have analyzed the genetic basis for T cell recognition of an endoge nous major histocompatibility complex class II-restricted self peptide . Transgenic mice expressing the influenza virus PR8 hemagglutinin I-E (d)-restricted determinant S1 (HA Tg mice) mediate negative selection of PR8 S1 specific T cells, but respond to immunization with a virus c ontaining a closely related analogue, S1(K113). Sequence analysis of S 1(K113)-specific T cell receptors (TCR) from nontransgenic mice reveal ed a dominant TCR clonotype that cross-reacts with PR8 S1. This clonot ype is eliminated by negative selection in HA Tg mice; nonetheless, mo dified versions of this TCR that used altered junctional sequences and a novel V alpha/V beta pairing to evade negative selection by the S1 self peptide were identified. The remaining S1(K113)-specific TCRs fro m HA Tg mice were highly diverse; 13 of 15 S1(K113)-specific TCRs from HA Tg mice used unique V alpha/V beta pairings. Thus, tolerance to PR 8 S1 as a self peptide does not limit the diversity of the T cell resp onse to S1(K113).