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Visceral leishmaniasis (VL) is a chronic and fatal disease in humans and dogs caused by the intracellular protozoan parasites,  Leishmania donovani  and  L. infantum  ( L. chagasi ). Relapse of disease is frequent in immunocompromised patients, in which the number of VL cases has been increasing recently. The present study is aimed to improve the understanding of mechanisms of  L. donovani  persistence in immunocompromised conditions using alymphoplastic  aly/aly  mice. Hepatic parasite burden, granuloma formation and induction of regulatory T cells were determined for up to 7 months after the intravenous inoculation with  L. donovani  promastigotes. While control  aly/+  mice showed a peak of hepatic parasite growth at 4 weeks post infection (WPI) and resolved the infection by 8 WPI,  aly/aly  mice showed a similar peak in hepatic parasite burden but maintained persistent in the chronic phase of infection, which was associated with delayed and impaired granuloma maturation. Although hepatic CD4 + Foxp3 +  but not CD8 + Foxp3 +  T cells were first detected at 4 WPI in both strains of mice, the number of CD4 + Foxp3 +  T cells was significantly increased in  aly/aly  mice from 8 WPI. Immunohistochemical analysis demonstrated the presence of Foxp3 +  T cells in  L. donovani –induced hepatic granulomas and perivascular neo-lymphoid aggregates. Quantitative real-time PCR analysis of mature granulomas collected by laser microdissection revealed the correlation of  Foxp3  and  IL-10  mRNA level. Furthermore, treatment of infected  aly/aly  mice with anti-CD25 or anti-FR4 mAb resulted in significant reductions in both hepatic Foxp3 +  cells and parasite burden. Thus, we provide the first evidence that CD4 + Foxp3 +  Tregs mediate  L. donovani  persistence in the liver during VL in immunodeficient murine model, a result that will help to establish new strategies of immunotherapy against this intracellular protozoan pathogen.

Involvement of CD4+ Foxp3+ Regulatory T Cells in Persistence of Leishmania donovani in the Liver of Alymphoplastic aly/aly Mice