Depletion of recipient CD4⁺ but not CD8⁺ T lymphocytes prevents the development of cardiac allograft vasculopathy

Background. We have described that chimeric rat hearts bearing recipient-type antigen-presenting cells (APCs) do not reject acutely, but develop cardiac allograft vasculopathy (CAV) in untreated recipients. This suggests that CAV is triggered either by CD8⁺ direct allorecognition or by CD4⁺ indirect allorecognition. To determine the allorecognition pathway responsible for CAV in this model, recipients of chimeric hearts underwent either CD8⁺ or CD4⁺ T cell depletion. Methods. Chimeric hearts were created via bone marrow transplantation in two fully major histocompatibility-mismatched rat strain combinations. DA recipients were thymectomized and treated with Ox8 and Ox38 murine monoclonal antibodies, which deplete CD8⁺ and CD4⁺ T cells, respectively. Chimeric PVG hearts bearing DA APCs, abbreviated PVG(DA), were heterotopically transplanted into recipients undergoing thymectomy alone or recipients undergoing thymectomy plus either CD4⁺ or CD8⁺ T cell depletion. Results. PVG(DA) allografts survived 100 days, but developed CAV in thymectomized recipients and in those permanently depleted of CD8⁺ T cells. In contrast, chimeric hearts transplanted into permanently CD4⁺ T cell-depleted recipients survived 100 days and demonstrated no evidence of CAV. Conclusions. In this specific strain combination, recipient CD8⁺ T cells are neither necessary nor sufficient for the development of CAV, whereas recipient CD4⁺ T cells are required for the development of CAV. These findings suggest that CAV is dependent on CD4⁺ indirect allorecognition and that CD8⁺ direct allorecognition stimulated by nonprofessional APCs plays a minor role.