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and Tumor Necrosis Factor in the Control of Leishmania donovani Infection
From the Immunology and Infection Laboratory and Australian Centre for International and Tropical Health and Nutrition,* Queensland Institute of Medical Research, Queensland, Australia; and the Immunology Unit, London School of Hygiene and Tropical Medicine, London, United Kingdom
Tumor necrosis factor (TNF) is critical for the control of visceral leishmaniasis caused by Leishmania donovani. However, the role of the related cytokine lymphotoxin (LT) 
in this infection is unknown. Here we report that C57BL/6 mice deficient in TNF (B6.TNF–/–) or LT (B6.LT–/–) have increased susceptibility to hepatic L. donovani infection. Furthermore, the outcome of infection in bone marrow chimeric mice is dependent on donor hematopoietic cells, indicating that developmental defects in lymphoid organs were not responsible for increased susceptibility to L. donovani. Although both LT and TNF regulated the migration of leukocytes into the sinusoidal area of the infected liver, their roles were distinct. LT was essential for migration of leukocytes from periportal areas, an event consistent with LT-dependent up-regulation of VCAM-1 on liver sinusoid lining cells, whereas TNF was essential for leukocyte recruitment to the liver. During visceral leishmaniasis, both cytokines were produced by radio-resistant cells and by CD4+ T cells. LT and TNF production by the former was required for granuloma assembly, while production of these cytokines by CD4+ T cells was necessary to control parasite growth. The production of inducible nitric oxide synthase was also found to be deficient in TNF- and LT-deficient infected mice. These results demonstrate that both LT and TNF are required for control of L. donovani infection in noncompensatory ways.
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