Activation and Maturation of Alloreactive CD4-Independent, CD8+ Cytolytic T Cells

Abstract

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.

Disparate Primary and Secondary Allospecific CD8+ T Cell Cytolytic Effector Function in the Presence or Absence of Host CD4+ T Cells

“…1b). These studies expand upon our previous observations that CD8 ϩ GICs in hepatocyte rejectors express a CTL phenotype (CD8 ϩ CD43 ϩ ) (47) and that the detection of in vivo allocytotoxicity correlates with graft survival status (46,47).…”

“…One study of cardiac allografts reported that host CD4 ϩ T cells are necessary to license dendritic cells for CD8 ϩ T cell activation, CTL function, and CD4-dependent graft rejection (45). However, the development of CTL effectors under CD4-independent conditions in response to allograft tissues such as skin, intestine, and hepatocytes has not been investigated, except for reports by our group showing that the rejection of allogeneic liver parenchymal cells in the absence of CD4 ϩ T cells is accompanied by in vivo cytotoxic effector function (46,47).…”

“…ϩ GICs in CD4 KO hepatocyte rejectors expresses the IL-2R␣ (CD25), implicating a role for local IL-2 in (CD4-independent) CD8 ϩ T cell alloimmunity (46,47). To address the possibility of enhanced CD8 ϩ T cell proliferation in the presence of CD4 ϩ T cells, we analyzed in vivo proliferation of allospecific TCR transgenic Des ϩ CD8 ϩ T cells in CD4-sufficient and CD4-deficient conditions.…”

Extracellular Hmgb1 Functions as an Innate Immune-Mediator Implicated in Murine Cardiac Allograft Acute Rejection

“…In contrast, although we observed a decreased number for the splenic CD4+IFNc -secreting T cells (Th1), but it was not statistically significant. This result suggests that Hmgb1-mediated cytotoxic T cell (CTL) activation could involve both Th1-dependent and independent mechanisms based on the fact that CTLs can be activated without the help of Th1 cells under certain conditions (40)(41)(42). Furthermore, a significantly decreased inflammatory infiltration accompanied by reduced IFNc expression was observed in the allograft after rA-box treatment ( Figures 5 and 6B).…”

Postnatal Expansion of the Pancreatic β-Cell Mass Is Dependent on Survivin

“…Mice harboring a conditionally targeted mouse survivin gene flanked by two loxP sites (survivin lox/lox ) have been described previously (16,27) (31). Morphometry and islet mass.…”