Antigen-Pulsed CpG-ODN-Activated Dendritic Cells Induce Host-Protective Immune Response by Regulating the T Regulatory Cell Functioning in Leishmania donovani-Infected Mice: Critical Role of CXCL10

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.

Gamma Interferon-Regulated Chemokines in Leishmania donovani Infection in the Liver

“…The latter observation highlights the variable actions reported for CXCL10, since, depending upon the pathogen, model, and organ examined (53), CXCL10 deletion or neutralization can have no effect on (54, 55), reduce (51,52,56), or apparently even enhance (57, 58) host resistance to infection. CXCL10 also influences and recruits suppressive CXCR3 ϩ regulatory T cells to the tissues (59,60), and the absence of CXCR3 ϩ regulatory T cells might enhance the control of L. donovani replication in CXCL10 Ϫ/Ϫ mice. That said, however, it is not clear why early-stage infection was better controlled in CXCL10 Ϫ/Ϫ mice than CXCR3 Ϫ/Ϫ mice, although mice of both backgrounds showed similarly deficient initial mononuclear cell recruitment.…”

Antibody Targeting of “Steady-State” Dendritic Cells Induces Tolerance Mediated by Regulatory T Cells

“…Finally, even without molecular transfection approaches, CpG-ODN-stimulated DCs exhibited pivotal proinflammatory functions, as in a Leishmania donovani model intracellular parasitic growth was abolished by these CpG-stimulated DCs ( 41 ). Alongside, it was observed that DC vaccination resulted in significant decreased Treg numbers.…”

Toll-Like Receptor Gene Expression during <i>Trichinella spiralis</i> Infection

“…CpG oligonucleotides (CpG ODNs) and CpG DNA can trigger intracellular signaling leading to the activation of macrophages, dendritic cells, and B cells, and the production of cytokines, chemokines, and immunoglobulins via TLR9 [ 7 ]. CpG ODNs have also been shown to stimulate the production of IL-10 by dendritic cells and promote the induction of T reg cells [ 17 ], and some parasite antigens can also initiate TLR9-dependent T reg cell activation [ 18 - 20 ]. T. spiralis has further been shown to induce T reg cell recruitment (with IL-10 and TGF-β as important cytokines) and regulate host Th2 and Th17 immune responses [ 4 ].…”