Allogeneic hematopoietic cell transplantation initiates atherosclerosis in mice via CD8+ T cells

Aims Patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) are at risk of developing graft-versus-host disease (GvHD) and are afflicted with an increased incidence of cardiovascular events. Whether allo-HCT contributes to atherosclerosis progression has not been addressed experimentally. Methods and results Here, we applied a novel minor histocompatibility antigen-(miHAg)-mismatch allo-HCT mouse model by transplanting C57BL/6 mice deficient for the low-density lipoprotein receptor (B6.Ldlr-/-) with bone marrow (BM) or BM and T cells (BMT) from BALB/b donors (BALB/b, H-2b → B6.Ldlr-/-, H-2b), and feeding recipients a Western diet. Mild clinical GvHD symptoms ensued with low disease activity in typical GvHD target organs. However, allogeneic BMT-recipients developed increased atherosclerotic lesions compared to mice receiving BM only or syngeneic BMT-recipients. Atherosclerotic lesions showed a heightened infiltration of effector CD8+ T cells in the aorta of BMT recipients. Furthermore, BMT recipients exhibited significantly higher serum cholesterol levels than BM recipients. Notably, CD8+ T cell depletion in B6.Ldlr-/- BMT recipients reduced atherosclerotic lesion formation and decreased cholesterol levels. Conclusions These data may provide a novel mechanistic underpinning for the clinically observed increased incidence of cardiovascular disease in long-term allo-HCT survivors. Moreover, we have identified CD8+ T cells as potential targets for mitigating GvHD-induced atherosclerosis.