Lymphotoxin αβ2 (membrane lymphotoxin) is critically important for resistance to Leishmania major infection in mice

Although the essential role of TNF-α in the control of intracellular pathogens including Leishmania major is well established, it is uncertain whether the related cytokine lymphotoxin αβ2 (LTα1β2, membrane lymphotoxin) plays any role in this process. In this study, we investigated the contribution of membrane lymphotoxin in host response to L. major infection by using LTβ-deficient (LTβ^-/-) mice on the resistant C57BL/6 background. Despite mounting early immune responses comparable to those of wild-type (WT) mice, LTβ^-/- mice developed chronic nonhealing cutaneous lesions due to progressive and unresolving inflammation that is accompanied by uncontrolled parasite proliferation. This chronic disease was associated with striking reduction in IL-12 and Ag-specific IFN-γ production by splenocytes from infected mice. Consistent with defective cellular immune response, infected LTβ^-/- mice had significantly low Ag-specific serum IgG1 and IgG2a levels compared with WT mice. Although administration of rIL-12 to L. major-infected LTβ^-/- mice caused complete resolution of chronic lesions, it only partially (but significantly) reduced parasite proliferation. In contrast, blockade of LIGHT signaling in infected LTβ^-/- mice resulted in acute and progressive lesion development, massive parasite proliferation, and dissemination to the visceral organs. Although infected LTβ^-/- WT bone marrow chimeric mice were more resistant than LTβ^-/- mice, they still had reduced ability to control parasites and showed defective IL-12 and IFN-γ production compared with infected WT mice. These results suggest that membrane lymphotoxin plays critical role in resistance to L. major by promoting effective T cell-mediated anti-Leishmania immunity.