Cross-primed CD8⁺T cells mediate graft rejection via a distinct effector pathway

To prevent bystander destruction of healthy host tissues, cytotoxic CD8⁺ T lymphocytes are fitted with specific receptors that direct their destructive forces specifically against chosen targets. We show here, however, that anti-H-Y monospecific, H-2^b-restricted MataHari CD8⁺ T cells reject H-2^k male skin grafts, with which they cannot directly interact. Such rejection is interferon-γ-dependent and only occurs if the recipient endothelium expresses H-2^b. The findings suggest an alternate indirect effector pathway that requires processing and presentation of the donor H-Y antigen by recipient endothelium and have implications for both transplantation and autoimmune disease.