Anergy and suppression regulate CD4(+) T cell responses to a self peptide

To examine the role of cognate peptide in establishing CD4(+) T cell tolera nce, we have mated transgenic mice that express the major I-E-d-restricted determinant (S1) from the influenza virus PR8 hemagglutinin (HA28 mice) wit h mice expressing a S1-specific T cell receptor (TS1 mice). Surprisingly, S 1-specific CD4(+) T cells were not substantially deleted in TS1xHA28 mice: indeed, lymph node cells expressing the S1-specific TCR were as abundant in TS1xHA28 mice as in TS1 mice. The S1-specific T cells in TS1xHA28 mice wer e, however, impaired in their ability to respond to S1 peptide both in vitr o and in vivo, and contained two distinct populations. Approximately half e xpressed a unique cell surface phenotype (CD25(hi)/CD45RB(int)) and had bee n anergized by the neo-self S1 peptide. The remainder responded normally to the S1 peptide if purified away from the anergic T cells, but their prolif eration was suppressed when the anergic T cells were also present in unfrac tionated lymph node cells or in mixed cultures. These findings establish th at anergy and suppression are coordinated mechanisms by which autoreactive CD4(+) T cells are regulated and that anergic/suppressor CD4(+) T cells can develop in response to self peptides.