Lymphotoxin alpha beta 2 (membrane lymphotoxin) is critically important for resistance to Leishmania major infection in mice

J Immunol. 2007 Oct 15;179(8):5358-66. doi: 10.4049/jimmunol.179.8.5358.

Abstract

Although the essential role of TNF-alpha in the control of intracellular pathogens including Leishmania major is well established, it is uncertain whether the related cytokine lymphotoxin alphabeta2 (LTalpha1beta2, 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 LTbeta-deficient (LTbeta(-/-)) mice on the resistant C57BL/6 background. Despite mounting early immune responses comparable to those of wild-type (WT) mice, LTbeta(-/-) 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-gamma production by splenocytes from infected mice. Consistent with defective cellular immune response, infected LTbeta(-/-) mice had significantly low Ag-specific serum IgG1 and IgG2a levels compared with WT mice. Although administration of rIL-12 to L. major-infected LTbeta(-/-) mice caused complete resolution of chronic lesions, it only partially (but significantly) reduced parasite proliferation. In contrast, blockade of LIGHT signaling in infected LTbeta(-/-) mice resulted in acute and progressive lesion development, massive parasite proliferation, and dissemination to the visceral organs. Although infected LTbeta(-/-) WT bone marrow chimeric mice were more resistant than LTbeta(-/-) mice, they still had reduced ability to control parasites and showed defective IL-12 and IFN-gamma 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Animals
  • Chronic Disease
  • Female
  • Immunity, Innate* / genetics
  • Leishmania major / growth & development
  • Leishmania major / immunology*
  • Leishmaniasis, Cutaneous / genetics
  • Leishmaniasis, Cutaneous / immunology*
  • Leishmaniasis, Cutaneous / parasitology
  • Leishmaniasis, Cutaneous / pathology
  • Lymphotoxin-alpha / physiology*
  • Lymphotoxin-beta / deficiency
  • Lymphotoxin-beta / genetics
  • Lymphotoxin-beta / physiology*
  • Macrophages / immunology
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Radiation Chimera / immunology
  • Radiation Chimera / parasitology

Substances

  • Lymphotoxin-alpha
  • Lymphotoxin-beta