Two distinct signals are required to activate T cells: an Ag-specific signal and a costimulatory signal mediated primarily by B7-1 (CD80) and B7-2 (CD86) through interactions with CD28. Costimulation appears to be critical in regulating autoreactive T cell responses. Here, we demonstrate that, in contrast to the parental uninfected T cell clone, a T cell clone infected by human T cell lymphotropic virus type I (HTLV-I) displays a remarkably enhanced response to Ag in the absence of B7 costimulation. Chinese hamster ovary cells either transfected with DRB1*1501 (t-DR2) alone or cotransfected with DR2 and either B7-1 or B7-2 were fixed, pulsed with myelin basic protein peptide 84-102 (MBPp84-102), and used as APCs. The MBPp84-102-reactive T cell clone Ob1A12.8 required costimulation with either B7-1 or B7-2 molecules, as the response to Ag was reduced by 90% in the absence of B7 costimulation. However, this requirement for B7 costimulation was abrogated after productive infection by HTLV-I. Stimulation of HTLV-I-infected T cells by MBPp84-102/t-DR2 induced the secretion of IL-5 and IFN-gamma, which approached the level induced in the presence of B7 costimulation, whereas IL-4 was induced to one third of its maximal level. Consistently, the secretion of IL-5 and IFN-gamma was not significantly inhibited by anti-B7-1 and B7-2 Abs, whereas IL-4 was inhibited by approximately 50%. In contrast, uninfected T cells required either B7-1 or B7-2 costimulation for significant cytokine secretion, and this response was inhibited by anti-B7-1 and B7-2 Abs. These findings suggest that HTLV-I-infected autoreactive T cells have the potential to induce an autoimmune response in the absence of B7 expression in the target organ. This may be of particular interest in the elucidation of HTLV-I pathogenicity given the association of HTLV-I infection with autoimmune-like diseases.