Cd8+ lymphocytes augment chronic rejection in a MHC class II mismatched model

Chronic rejection, or cardiac allograft vasculopathy (CAV), remains the leading cause of late death in heart transplant recipients. The precise role and contributions of T lymphocyte subsets to CAV development remains unknown. Methods. Donor hearts from B6.C-H2(bm12) mice were transplanted into T lymphocyte subset knockout recipients and T lymphocyte-reconstituted nude recipients. No immunosuppression was used. Intimal proliferation was measured morphometrically. In vitro studies were performed to analyze the donor-specific activation status of recipient CD8(+) lymphocytes by examining cellular proliferation, interleukin-a secretion, and interleukin-2R alpha expression. Intracellular cytokine staining assay was performed to determine both the profile and source of intragraft cytokines, Results. Hearts transplanted into wild-type recipients developed severe CAV by 24 days, Intimal lesions were absent in the hearts that were transplanted into nude and CD4-/- knockout mice (containing CD8(+) lymphocytes), In contrast, the donor hearts in CD8-/knockout recipients (containing CD4(+) lymphocytes) developed CAV, but significantly less than in wildtype, Adoptive transfer of T lymphocyte subset populations into nude recipients confirmed that CAV was absolutely contingent on CD4(+) lymphocytes, and that CD8(+) lymphocytes played an additive role in intimal lesion progression in the presence of CD4(+) lymphocytes, Although CD8(+) lymphocytes alone did not cause CAV in vivo, we demonstrated that MHC class II disparate alloantigens activated CD8(+) lymphocytes both in vivo and in vitro. Finally, both CD4(+) and CD8(+) lymphocytes contributed to the intragraft IL-2 and IFN-gamma production. Conclusions. In this MHC class II mismatched murine model, CAV is a T lymphocyte dependent event, and absolutely contingent on the presence of CD4(+) lymphocytes, Furthermore, CD8(+) lymphocytes (1) are activated by MHC class II disparate antigens and (2) play a significant role in the progression of lesion development. Finally, both CD4(+) and CD8(+) lymphocytes contribute to CAV development via secretion of IFN-gamma, a known mediator of CAV this model.