Activation and maturation of alloreactive CD4-independent, CD8⁺ cytolytic T cells

The goal of this study was to determine the in vivo conditions that promote activation of the (CD4-independent) CD8⁺ T cell-mediated rejection pathway. We have previously noted that hepatocellular but not islet allografts readily activate this rejection pathway. In the current study, we utilized these two cell transplant models to investigate whether differences in host cell recruitment to the graft site, expression of T-cell activation markers by CD8⁺ graft infiltrating cells (GICs), and/or development of delayed-type hypersensitivity (DTH) and cytotoxic T lymphocyte cell-mediated effector functions could account for the differential transplant outcomes. The collective results demonstrate that recruitment of CD8⁺ T cells to the site of transplant, CD103 or CD69 expression on CD8⁺ GICs, and activation of alloreactive DTH responses are insufficient to initiate CD4-independent, CD8-dependent transplant rejection. Instead, rejection by alloreactive (CD4-independent) CD8⁺ T cells correlated with expression of CD25, CD154 and CD43 by CD8⁺ GICs, in vitro alloproliferation by recipient CD8⁺ T cells, and the development of in vivo allospecific cytolytic effector function. These results suggest that tissue-derived factors influence the activation and maturation of (CD4-independent) CD8⁺ T cells into cytolytic effectors, which correlates with transplant rejection.