TNF contributes to the immunopathology of perforin/Fas ligand double deficiency.

Perforin (pfp)/Fas ligand (FasL) double-deficient mice have previously been shown to be infertile, lose weight and die prematurely due to tissue destruction caused by a significant inflammatory infiltrate of monocytes/macrophages and T cells. Herein we have compared disease progression in mice additionally deficient in the inflammatory mediator TNF. Unlike pfp/FasL double-deficient mice (TNF+/+ pfp-/- gld), mice lacking functional TNF, FasL and pfp (TNF-/- pfp-/- gld) were comparatively fertile, with the majority of mice not suffering severe pancreatitis or hysterosalphingitis in the first 5 months of life. The mean lifespan of TNF-/- pfp-/- gld mice was 217 +/- 79 days compared with 69 +/- 10 days for TNF+/+ pfp-/- gld mice and the majority of moribund TNF-/- pfp-/- gld mice appeared to die as a result of severe pancreatitis, suggesting that loss of TNF was not completely protective. At 8 weeks of age, characteristics associated with the gld phenotype, such as expansion of B220+ CD4- CD8- T cells, lymphadenopathy and hypergammaglobulinemia were comparable between TNF+/+ pfp-/- gld and TNF-/- pfp-/- gld mice, although the lymphoid organs of TNF+/+ pfp-/- gld mice contained greater numbers of B220+ CD4- CD8- T cells, macrophages and T cells. We conclude that TNF is necessary for the full manifestation of immune dysregulation caused by pfp/FasL-deficiency, in particular in the early and overwhelming tissue infiltration and destruction caused by inflammatory cells.