The magnitude of acute hepatitis is more limited by regulation of cytokine signalling than apoptosis of liver-infiltrating effector CD8 T cells (P4174)

Abstract

Abstract Acute hepatitis is often mediated by CD8 T cells that kill target cells or secrete hepatotoxic cytokines. However, the parameters regulating CD8 T cell-mediated acute hepatitis are not well understood. We used the well-characterized Met-Kb Tg mouse model of acute hepatitis, in which hepatitis is mediated by lymph node activated TCR Tg CD8 recognizing their cognate antigen in the liver. To investigate whether cytokine regulation or apoptosis of CD8 T cells were critical in limiting acute hepatocellular injury, adoptive transfer experiments were performed using TCR Tg T cells deficient for either suppressor of cytokine signaling (SOCS-1) or the pro-apoptotic molecule Bim. Although there was a substantial accumulation of Bim-/- Tg cells, the outcome of hepatitis remained unchanged, suggesting that effector T cell survival was not a critical parameter in limiting liver damage. In contrast, SOCS-1-/- Tg T cells induced a heightened severity of hepatitis than their wt counterparts. SOCS-1-/- Tg cells isolated from the liver displayed upregulated IL-2Rα, required for the high affinity IL-2 receptor, and was associated with higher levels of IFN-γ expression, CTL activity, and proliferation rates, consistent with enhanced effector function. These data support a critical role for cytokines in CTL function, and demonstrate that the propensity of CD8 T cells to mediate acute hepatitis is determined by the quality rather than the number of CTLs infiltrating the liver.