To examine the role of cognate peptide in establishing CD4⁺ T cell tolerance, we have mated transgenic mice that express the major I‐E^d‐restricted determinant (S1) from the influenza virus PR8 hemagglutinin (HA28 mice) with mice expressing a S1‐specific T cell receptor (TS1 mice). Surprisingly, S1‐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 were, however, impaired in their ability to respond to S1 peptide both in vitro and in vivo, and contained two distinct populations. Approximately half expressed a unique cell surface phenotype (CD25^hi / CD45RB^int) and had been 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 proliferation was suppressed when the anergic T cells were also present in unfractionated lymphnode cells or in mixed cultures. These findings establish that 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.