Coexpression of Donor Peptide/Recipient MHC Complex and Intact Donor MHC: Evidence for a Link between the Direct and Indirect Pathways

T lymphocytes recognize foreign antigens presented by donor or recipient cells through the direct and indirect pathways respectively. This raises the question of how directly and indirectly activated T cells interact. A 4-cell model involving the interaction of CD4+ and CD8+ T cells recognizing major histocompatibility complex (MHC) class II on recipient antigen presenting cell (APC), and MHC class I on donor APC, has been proposed. However, this would require complex co-ordination between all the participating cell types. The semidirect pathway of alloantigen presentation suggests a simpler mechanism. Although exchange of MHC class II molecules between donor and recipient cells has been described, coexpression of recipient MHC molecules presenting donor derived allopeptides (indirect presentation) and donor MHC (direct presentation) on the same cell, a key requirement for the semidirect alloantigen presentation pathway, has not been demonstrated. We have used a mouse transplantation model to demonstrate the presence of cells expressing both donor MHC class I/II molecules, and a donor MHC class II peptide in the context of a recipient MHC class II molecule. This would allow indirectly activated CD4+ T cells to regulate directly activated CD4+ T cells, or to help directly activated CD8+ T cells, thus providing physical evidence for the semidirect pathway.