Differential Requirements for Soluble and Transmembrane Tumor Necrosis Factor in the Immunological Control of Primary and Secondary Listeria monocytogenes Infection

The relative contributions of transmembrane tumor necrosis factor (memTNF)and soluble tumor necrosis factor (solTNF) in innate and adaptiveimmunity are poorly defined. We examined the capacities of wild-type(WT) mice, TNF⁻/⁻ mice, and memTNF mice,which express only transmembrane TNF, to control primary and secondaryListeria monocytogenes infections. Soluble TNF was notrequired for induction or maintenance of protective immunity against alow-dose (200-CFU) Listeria infection. In contrast toTNF⁻/⁻ mice, both WT and memTNF mice clearedthe bacilli within 10 days and were fully protected against rechallengewith a lethal infective dose. Furthermore, T cells transferred fromimmune mice, but not from naïve, WT, and memTNF mice, protectedTNF⁻/⁻ recipients against an otherwiselethal infection. By contrast, infection with a higher dose ofListeria (2,000 CFU) clearly demonstrated that solTNF isrequired to coordinate an optimal protective inflammatory response.memTNF mice were more susceptible to a high-dose infection, and theyexhibited delayed bacterial clearance, increased inflammation, andnecrosis in the liver that resulted in 55% mortality. The dysregulatedinflammation was accompanied by prolonged elevated expression of mRNAsfor several chemokines as well as the macrophage effector moleculesinducible nitric oxide synthase and LRG-47 in the livers of memTNF micebut not in the livers of WT mice. These data demonstrated that memTNFis sufficient for establishing protective immunity against a primarylow-dose Listeria infection but that solTNF is required foroptimal control of cellular inflammation and resistance to a primaryhigh-dose infection. By contrast, memTNF alone is sufficient forresolution of a secondary, high-dose infection and for the transfer ofprotective immunity with memory Tcells.