Abstract
Visceral leishmaniasis (VL), caused by Leishmania donovani, is a systemic infection of reticulo-endothelial system. There is currently no protective vaccine against VL and chemotherapy is increasingly limited due to appearance of drug resistance to first line drugs such as antimonials and amphotericin B. In the present study, by using a murine model of leishmaniasis we evaluated the function played by soluble leishmanial antigen (SLA)-pulsed CpG-ODN-stimulated dendritic cells (SLA–CpG–DCs) in restricting the intracellular parasitic growth. We establish that a single dose of SLA–CpG–DC vaccination is sufficient in rendering complete protection against L. donovani infection. In probing the possible mechanism, we observe that SLA–CpG–DCs vaccination results in the significant decrease in Foxp3+GITR+CTLA4+CD4+CD25+ regulatory T cells (Treg) cell population in Leishmania-infected mice. Vaccination with these antigen-stimulated dendritic cells results in the decrease in the secretion of TGF-β by these Treg cells by possible regulation of the SMAD signaling. Moreover, we demonstrate that a CXC chemokine, IFN-γ-inducible protein 10 (IP-10; CXCL10), has a direct role in the regulation of CD4+CD25+ Treg cells in SLA–CpG–DC-vaccinated parasitized mice as Treg cells isolated from IP-10-depleted vaccinated mice showed significantly increased TGF-β production and suppressive activity.
Highlights
Visceral leishmaniasis (VL), a neglected tropical disease is caused by Leishmania donovani, a protozoan parasite [1, 2]
inducible protein 10 (IP-10) DEPLETION ABROGATES THE TGF-β SIGNALING IN CD4+CD25+ Treg CELLS IN soluble leishmanial antigen (SLA)–CpG–DC-VACCINATED PARASITIZED MICE We have previously demonstrated that the induction of antileishmanial protective immunity by SLA–CpG–DCs is entirely dependent on IP-10 [5]
To establish whether SMAD4 is involved in the SLA–CpG– DC-mediated regulation of TGF-β signaling in CD4+CD25+ Treg cells, we studied the phosphorylation of SMAD4 in CD4+CD25+ Treg cells during SLA–CpG–DC vaccination
Summary
Visceral leishmaniasis (VL), a neglected tropical disease is caused by Leishmania donovani, a protozoan parasite [1, 2]. We have previously reported that mice vaccinated with a single dose of soluble leishmanial antigen (SLA)-pulsed DC stimulated with CpG oligodeoxynucleotides or CpG-ODN (SLA–CpG–DCs) were protected against a subsequent leishmanial challenge [5]. Stimulation with CpG-ODN, a TLR9 ligand along with SLA activates the dendritic cells and results in the development of Leishmania antigen-specific cytotoxic T lymphocytes, which destroys the parasite in vivo [5]. Earlier from our lab, we have demonstrated that exogenously administered CXCL10 besides regulating the intracellular parasitic load can regulate the CD4+CD25+ regulatory T cells (Treg) cells in Leishmania-infected mice [9]. We have investigated the potential role of SLA– CpG–DCs vaccination in the regulation of immunosuppressive CD4+CD25+ Treg cells in Leishmania-infected mice
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