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2 (Membrane Lymphotoxin) Is Critically Important for Resistance to Leishmania major Infection in Mice1
* Department of Immunology, and
Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada;
Comparative Genomics Centre, School of Pharmacy and Molecular Sciences/School of Veterinary and Biomedical Sciences, James Cook University, Townsville, Australia; and
Department of Pathology, University of Chicago, Chicago, IL 60637
Although the essential role of TNF-
in the control of intracellular pathogens including Leishmania major is well established, it is uncertain whether the related cytokine lymphotoxin 
2 (LT12, 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 LT-deficient (LT–/–) mice on the resistant C57BL/6 background. Despite mounting early immune responses comparable to those of wild-type (WT) mice, LT–/– 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-
production by splenocytes from infected mice. Consistent with defective cellular immune response, infected LT–/– mice had significantly low Ag-specific serum IgG1 and IgG2a levels compared with WT mice. Although administration of rIL-12 to L. major-infected LT–/– mice caused complete resolution of chronic lesions, it only partially (but significantly) reduced parasite proliferation. In contrast, blockade of LIGHT signaling in infected LT–/– mice resulted in acute and progressive lesion development, massive parasite proliferation, and dissemination to the visceral organs. Although infected LT–/– WT bone marrow chimeric mice were more resistant than LT–/– mice, they still had reduced ability to control parasites and showed defective IL-12 and IFN- 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the Canadian Institutes for Health Research), Canadian Foundation for Innovation, and Manitoba Health Research Council, Establishment Grant). J.E.U. is a recipient of the Canadian Institutes for Health Research New Investigator Award.
2 Current address: Department of Immunology, Third Military University, Chongqing, People’s Republic of China.
3 Address correspondence and reprint requests to Dr. Jude E. Uzonna, Department of Immunology, University of Manitoba, 730 William Avenue, Winnipeg, Manitoba, Canada. E-mail address: uzonna{at}cc.umanitoba.ca
4 Abbreviations used in this paper: LT, lymphotoxin; BMDM, bone marrow-derived macrophage; BMDC, bone marrow-derived dendritic cell; DC, dendritic cell; mLT, membrane LT; HVEM, herpes virus entry mediator; LIGHT, ligand homologous to LT, exhibits inducible expression, competes with herpes simplex virus glycoprotein D for HVEM, a receptor expressed by T lymphocytes; SLA, soluble Leishmania Ag; WT, wild type.
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  J. M. Ehrchen, J. Roth, K. Roebrock, G. Varga, W. Domschke, R. Newberry, C. Sorg, C. Muller-Tidow, C. Sunderkotter, T. Kucharzik, et al. The Absence of Cutaneous Lymph Nodes Results in a Th2 Response and Increased Susceptibility to Leishmania major Infection in Mice Infect. Immun., September 1, 2008; 76(9): 4241 - 4250. [Abstract] [Full Text] [PDF]
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