The elusive Mls gene(s) are mouse mammary tumor virus genes. The endogenous cotolerogen involved in the clonal deletion of Tcr V(beta)5.1, 5.2, and 11 in H-2E+ mouse strains has been narrowed down to MTV-9. We demonstrate that similar to H-2E(alpha) molecules, human DQw6(beta) chain mediated clonal deletion of Tcr V(beta)5.1, 5.2, and 11 also requires the MTV-9 gene product. This shows that human class II molecules can present mouse retroviral antigen. Further, backcross analysis involving [B10.M(DQb) x DBA/1] suggest a second cotolerogen in the B10.M background in the clonal deletion of V(beta)5-bearing T cells.