LOW AVIDITY RECOGNITION OF A CLASS II-RESTRICTED NEO-SELF PEPTIDE BY VIRUS-SPECIFIC T-CELLS

The specificity with which CD4(+) T cells recognize self peptides in v ivo was examined in transgenic mice that express an influenza virus PR 8 hemagglutinin (HA) polypeptide in many tissues, including the thymus (HA Tg mice). HA Tg and non-Tg mice were analyzed for their T cell re sponses to the major PR8 HA I-E(d)-restricted CD4(+) T cell determinan t S1, Negative selection eliminated S1-specific T cells from HA Tg mic e. Nevertheless, HA Tg mice retained the ability to mount a T cell res ponse to a closely related analog of the S1 determinant [S1(K113)1, an d some S1(K113)-specific TCRs displayed a partial reactivity with S1 a s indicated by their ability to transmit signals for IL-3 but not IL-2 secretion in response to the neo-self peptide. Moreover, the neo-self S1 peptide antagonized the ability of these TCRs to signal IL-2 secre tion in response to the foreign S1(K113) determinant. Thus, TCRs that exhibit a partial reactivity with a self peptide are present in the pe ripheral T cell repertoire and can be activated by a virus containing an analog of the self peptide. These findings provide a model for the induction of autoimmunity by viruses that are close homologs of self p eptides, and suggest a way in which Tons could react with self peptide s during positive selection of developing thymocytes.