Distinct roles for lymphotoxin-α and tumor necrosis factor in the control of leishmania donovani infection

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) a in this infection is unknown. Here we report that C57BL/6 mice deficient in TNF (B6.TNF-/-) or LTalpha (B6.LTbeta(-/-)) 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 LTalpha and TNF regulated the migration of leukocytes into the sinusoidal area of the infected liver, their roles were distinct. LTalpha was essential for migration of leukocytes from periportal areas, an event consistent with LTalpha-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. LTalpha 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 LTalpha-deficient infected mice. These results demonstrate that both LTalpha and TNF are required for control oft. donovani infection in noncompensatory ways.