CD154+ graft antigen-specific CD4+ T cells are sufficient for chronic rejection of minor antigen incompatible heart grafts

We used a defined model system to address the role of minor histocompatibility antigen-specific CD4+ T cells in chronic rejection. The coronary arteries of vascularized heart grafts expressing the model antigen ovalbumin developed intimal hyperplasia in normal recipients and those lacking CD8+ T cells but not in those lacking CD4+ T cells. Furthermore, purified ovalbumin-specific CD4+ T cells from T-cell antigen receptor transgenic mice caused intimal hyperplasia in ovalbumin-expressing heart grafts in lymphocyte-deficient mice. The graft antigen-specific CD4+ T cells only caused intimal hyperplasia when expressing CD154 and were found in the intima of the affected coronary arteries along with CD40+ cells, CD11c+ dendritic cells and CD11b+, Gr-1+ monocytes. These results show that minor histocompatibility antigen-specific CD4+ T cells are required to cause the classical vascular changes of chronic rejection. They are capable of doing so without contributions from other lymphocytes, and may cause intimal hyperplasia by using CD154 to stimulate other non-lymphoid cells in the intima.