CD8+ lymphocytes augment chronic rejection in a MHC class II mismatched model

Area of Science:

• Immunology
• Transplantation Biology
• Cardiovascular Research

Background:

• Chronic rejection, known as cardiac allograft vasculopathy (CAV), is the primary cause of late mortality in heart transplant recipients.
• The specific roles of different T lymphocyte subsets in CAV development are not fully understood.

Purpose of the Study:

• To elucidate the contributions of CD4+ and CD8+ T lymphocyte subsets to the development and progression of cardiac allograft vasculopathy (CAV).

Main Methods:

• Utilized a murine model involving transplantation of donor hearts into T lymphocyte subset knockout recipients without immunosuppression.
• Assessed intimal proliferation morphometrically and analyzed donor-specific T cell activation in vitro.
• Investigated intragraft cytokine production using intracellular cytokine staining.

Main Results:

• Severe CAV developed in wild-type recipients, but was absent in CD4-/- knockout recipients (with CD8+ cells).
• CAV occurred in CD8-/- knockout recipients (with CD4+ cells), but was significantly less severe than in wild-type.
• CD4+ T cells were essential for CAV, while CD8+ T cells played an additive role in lesion progression.
• MHC class II disparate alloantigens activated CD8+ T cells, and both CD4+ and CD8+ T cells produced IL-2 and IFN-gamma.

Conclusions:

• CAV is a T lymphocyte-dependent process absolutely contingent on CD4+ T cells in this MHC class II mismatched model.
• CD8+ T cells are activated by MHC class II disparate antigens and significantly contribute to lesion progression.
• Both CD4+ and CD8+ T cells contribute to CAV development through IFN-gamma secretion.