Cytotoxic effector function of CD4-independent, CD8⁺ T cells is mediated by TNF-α/TNFR

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.