Background

Liver parenchymal cell allografts initiate both CD4-dependent and CD4-independent, CD8+ T cell–mediated acute rejection pathways. The magnitude of allospecific CD8+ T cell in vivo cytotoxic effector function is maximal when primed in the presence of CD4+ T cells. The current studies were conducted to determine if and how CD4+ T cells might influence cytotoxic effector mechanisms.

Methods

Mice were transplanted with allogeneic hepatocytes. In vivo cytotoxicity assays and various gene-deficient recipient mice and target cells were used to determine the development of Fas-, TNF-α-, and perforin-dependent cytotoxic effector mechanisms after transplantation.

Results

CD8+ T cells maturing in CD4-sufficient hepatocyte recipients develop multiple (Fas-, TNF-α-, and perforin-mediated) cytotoxic mechanisms. However, CD8+ T cells, maturing in the absence of CD4+ T cells, mediate cytotoxicity and transplant rejection that is exclusively TNF-α/TNFR-dependent. To determine the kinetics of CD4-mediated help, CD4+ T cells were adoptively transferred into CD4-deficient mice at various times posttransplant. The maximal influence of CD4+ T cells on the magnitude of CD8–mediated in vivo allocytotoxicityf occurs within 48 hours.

Conclusion

The implication of these studies is that interference of CD4+ T cell function by disease or immunotherapy will have downstream consequences on both the magnitude of allocytotoxicity as well as the cytotoxic effector mechanisms used by allospecific CD8+ cytolytic T cells.