Defective co-stimulation and impaired Th1 development in tumor necrosis factor lymphotoxin-α double-deficient mice infected with Candida albicans

To define the immunological functions of tumor necrosis factor (TNF) in Candida albicans infection, TNF/lymphotoxin (LT)-alpha double-deficient mice were assessed for susceptibility to systemic or gastrointestinal infection and parameters of innate and adaptive T-h immunity. When compared to wild-type mice, TNF/LT-alpha-deficient mice were more susceptible to either type of infection caused by virulent or low-virulence C. albicans cells. Susceptibility to infection correlated with impaired development of protective T(h)1 responses, in spite of the production of bioactive IL-12. The occurrence of predominant T(h)2 responses was associated with both impaired antifungal effector functions of neutrophils and a defective expression of co-stimulatory molecules on macrophages. All functions were improved upon administration of recombinant TNF-alpha, also resulting in increased resistance to infection, These findings indicate that the protective effect of TNF-alpha in candidiasis relies on the induction of antifungal T(h)1 responses, possibly occurring through stimulation of antifungal effector functions and co-stimulatory activities of phagocytic cells.