CD4 T cells mediate cardiac xenograft rejection via host MHC Class II

• Published in: The Journal of heart and lung transplantation Vol. 31; no. 9; pp. 1018 - 1024
• Main Authors: Plenter, Robert J, Grazia, Todd J., MD, Doan, An N., BS, Gill, Ronald G., PhD, Pietra, Biagio A., MD
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.09.2012; Elsevier
• Subjects: Animals; antigen presentation/processing; Biological and medical sciences; Cardiology. Vascular system; CD4-Positive T-Lymphocytes - immunology; Female; Graft Rejection - immunology; Heart Transplantation - immunology; Histocompatibility Antigens Class II - immunology; Medical sciences; MHC; Mice; Rats; Surgery; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Surgery of the heart; T cell; transplantation; Transplantation, Heterologous - immunology; MHC; antigen presentation/processing; T cell; transplantation; Heart; Graft(material); Class II histocompatibility antigen; Transplantation; Heterograft; Heterotransplantation; Phlebology; Rejection; Treatment; Surgery; T-Lymphocyte; Graft; Circulatory system; Cardiology
• ISSN: 1053-2498; 1557-3117
• DOI: 10.1016/j.healun.2012.05.018

Background Previous studies have shown that acute CD4 T-cell–mediated cardiac allo graft rejection requires donor major histocompatibility complex (MHC) Class II expression and can be independent of “indirect” antigen presentation. However, other studies suggested that indirect antigen presentation to CD4 T cells may play a primary role in cellular xeno graft immunity. Thus, the relative roles of direct/indirect CD4 T cell reactivity against cardiac xenografts are unclear. In this study we set out to determine the role for indirect CD4 T cell reactivity in cardiac xenograft rejection. Methods Rat hearts were transplanted heterotopically into wild-type and immunodeficient mice. Recipients were untreated, treated with depleting antibodies, or reconstituted with wild-type cells. Results Antibody depletion confirmed that rat heart xenograft rejection in C57Bl/6 mice was CD4 T-cell-dependent. Also, heart xenografts survived long term in B6 MHC Class II (C2D)-deficient mice. Graft acceptance in C2D mice was not secondary to CD4 T cell deficiency alone, because transferred B6 CD4 T cells failed to trigger rejection in C2D hosts. Furthermore, purified CD4 T cells were sufficient for acute rejection of rat heart xenografts in immune-deficient B6 rag1 −/− recipients. Importantly, CD4 T cells did not reject rat hearts in C2D rag1 −/− hosts, in contrast to results using cardiac allografts. “Direct” xenoreactive CD4 T cells were not sufficient to mediate rejection despite vigorous reactivity to rat stimulator cells in vitro. Conclusions Taken together, our results show that CD4 T cells are both necessary and sufficient for acute cardiac xenograft rejection and that host MHC Class II is critical in this process.