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.
- CD4 T cells
- CD8 T cells