IL-5 and eosinophils mediate the rejection of fully histoincompatible vascularized cardiac allografts: regulatory role of alloreactive CD8+ T lymphocytes and IFN-γ

CD8 + T lymphocytes are known to inhibit the development of eosinophilia and IL-5 synthesis in models of experimental lung disease. In transplantation, the rejection of fully mismatched cardiac allografts by recipients depleted of CD8 + T cells is characterized by the recruitment of eosinophils in the rejected organs. We show here that this intragraft eosinophilia is dependent on the production of IL-5 since hearts transplanted into IL-5-deficient recipients depleted of CD8 + cells did not contain eosinophils. More importantly, allograft survival was significantly extended in these animals. In mixed lymphocyte cultures (MLC), the presence of CD8 + T cells in the responding cell population inhibited the secretion of IL-5. This inhibition was IFN-+ dependent since adding neutralizing anti-IFN-+ antibodies induced the production of IL-5. Furthermore, spleen cells isolated from IFN-+ receptor (IFN-+ R)-deficient mice secreted IL-5 upon allogeneic stimulation in primary MLC. In vivo, eosinophilia was observed in allografts rejected by IFN-+ R-deficient recipients. On the contrary, grafts rejected by IFN-+ R-deficient mice treated with neutralizing anti-IL-5 antibodies did not exhibit eosinophilic infiltration. Our study reveals the capacity of IL-5-secreting CD4 + T cells and eosinophils to promote the rejection of heart allograft and demonstrates the importance of CD8 + T cells and IFN-+ in regulating this pathway of rejection.