To follow the fate of alloreactive T cell effectors in graft-vs-host disease, L d-specific CD8+ T cells from C57BL/6 2C TCR-transgenic donors were transplanted into sublethally irradiated (750 cGy) L d+ or L d− recipients. In L d− C57BL/6 or (BALB/c-dm2× C57BL/6) F 1 recipients, naive 2C T cells engrafted and survived long term, but did not acquire effector function. In L d+(BALB/c× C57BL/6) F 1 recipients, 2C T cells engrafted, expanded, became cytolytic, destroyed host B cells and double-positive thymocytes, and later disappeared. Despite marked damage to lymphoid and hemopoietic cells by 2C T cells, no significant pathology was detected in other organs, and recipients survived. L d+(BALB/c× C57BL/6) F 1 recipients died when LPS/endotoxin was administered on day 7 after cell transfer, while L d−(BALB/c-dm2× C57BL/6) F 1 recipients survived. Our findings show that under certain conditions, a CD8+ T cell population recognizing an extremely limited repertoire of Ags can initiate graft-vs-host disease.