Independent Protective Effects for Tumor Necrosis Factor and Lymphotoxin Alpha in the Host Response to Listeria monocytogenes Infection

Although the essential role of tumor necrosis factor (TNF) in resistance to Listeria monocytogenes infection is well established, the roles of the related cytokines lymphotoxin alpha (LT[alpha]) and lymphotoxin beta (LT{szligbeta}) are unknown. Using C57BL/6 mice in which the genes for these cytokines were disrupted, we examined the contributions of TNF, LT[alpha], and LT{szligbeta} in the host response to LISTERIA: To overcome the lack of peripheral lymph nodes in LT[alpha][superscript -/-] and LT{szligbeta}[superscript -/-] mice, bone marrow chimeras were constructed. TNF[superscript -/-] and LT[alpha][superscript -/-] chimeras that lacked both secreted LT[alpha]₃ and membrane-bound LT[alpha]₁{szligbeta}₂ and LT[alpha]₂{szligbeta}₁ were highly susceptible and succumbed 4.5 and 6 days, respectively, after a low-dose infection (200 CFU). LT{szligbeta}[superscript -/-] chimeras, which lacked only membrane-bound LT, controlled the infection in a manner comparable to wild-type (WT) chimeras. The Listeria-specific proliferative and gamma interferon T-cell responses were equivalent in all five groups of infected mice (LT[alpha][superscript -/-] and LT{szligbeta}[superscript -/-] chimeras, WT chimeras, and TNF[superscript -/-] and WT mice). TNF[superscript -/-] mice and LT[alpha][superscript -/-] chimeras, however, failed to generate the discrete foci of lymphocytes and macrophages that are essential for bacterial elimination. Rather, aberrant necrotic lesions comprised predominantly of neutrophils with relatively few lymphocytes and macrophages were observed in the livers and spleens of TNF[superscript -/-] and LT[alpha][superscript -/-] chimeras. Therefore, in addition to TNF, soluble LT[alpha]₃ plays a separate essential role in control of listerial infection through control of leukocyte accumulation and organization in infected organs.