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- Title
Involvement of CD4<sup>+</sup> Foxp3<sup>+</sup> Regulatory T Cells in Persistence of Leishmania donovani in the Liver of Alymphoplastic aly/aly Mice.
- Authors
Tiwananthagorn, Saruda; Iwabuchi, Kazuya; Ato, Manabu; Sakurai, Tatsuya; Kato, Hirotomo; Katakura, Ken
- Abstract
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. Author Summary: The protozoan parasite Leishmania donovani is the causative agent of visceral leishmaniasis (VL) with a variety of outcomes ranging from asymptomatic to fatal infection. In the last decade, an increasing number of VL cases in immunocompromised conditions have been reported. Loss of the control of parasite persistence causes relapse of the disease in these patients. To clarify why parasite persistence and disease are caused in an immunocompromised condition, we examined L. donovani infection in alymphoplastic aly/aly mice that completely lack lymph nodes and have disturbed spleen architecture. Although parasites grew in the liver of aly/+ mice for the first 4 weeks post infection (WPI) and parasites were eliminated by 8 WPI, we found that parasites persisted in the liver of aly/aly mice with the ineffective of granuloma formation to kill the parasites. These aly/aly mice showed significant increases in CD4+Foxp3+ regulatory T cells in the liver. Consequently, we treated infected mice with anti-CD25 or anti-FR4 mAb to inhibit the function of Tregs, and found significant reductions in both hepatic Foxp3+ cells and parasite burden. These results clearly demonstrated for the first time that the expansion of CD4+Foxp3+ Tregs is involved in hepatic L. donovani persistence in immunodeficient murine model.
- Publication
PLoS Neglected Tropical Diseases, 2012, Vol 6, Issue 8, p1
- ISSN
1935-2727
- Publication type
Academic Journal
- DOI
10.1371/journal.pntd.0001798