Mycoplasma arthritidis generates a soluble, non-dialysable, polyclonal mitogen which is active for murine and human T lymphocytes in the presence of an adherent, radio-resistant, Ia-bearing accessory cell population. Genetic analysis has established that the I-E sub-region of the murine H2 gene complex controls responses to the mitogen and that this control is exercised at the level of the Ia-bearing accessory cell. Lymphocyte proliferation, induction of cytotoxic lymphocytes, and interferon induction are all under Ir gene control and appear to be dependent upon binding of the mitogen to a specific Ia antigen present on a subset of splenic cells. This mycoplasma mitogen provides a new model system to define the mechanisms of Ir gene control of lymphocyte activation.