IL-10 from Regulatory T Cells Determines Vaccine Efficacy in Murine Leishmania major Infection

Abstract

Leishmaniasis affects 12 million people, but there are no vaccines. Immunological correlates of vaccine efficacy are unclear. Polarized Th1 vs Th2 responses in Leishmania major-infected mice suggested that a shift in balance from IL-4 to IFN-γ was the key to vaccine success. Recently, a role for IL-10 and regulatory T cells in parasite persistence was demonstrated, prompting re-evaluation of vaccine-induced immunity. We compared DNA/modified vaccinia virus Ankara heterologous prime-boost with Leishmania homolog of the receptor for activated C kinase (LACK) or tryparedoxin peroxidase (TRYP). Both induced low IL-4 and high IFN-γ prechallenge. Strikingly, high prechallenge CD4 T cell-derived IL-10 predicted vaccine failure using LACK, whereas low IL-10 predicted protection with TRYP. The ratio of IFN-γ:IL-10 was thus a clear prechallenge indicator of vaccine success. Challenge infection caused further polarization to high IL-10/low IFN-γ with LACK and low IL-10/high IFN-γ with TRYP. Ex vivo quantitative RT-PCR and in vitro depletion and suppression experiments demonstrated that Ag-driven CD4+CD25+ T regulatory 1-like cells were the primary source of IL-10 in LACK-vaccinated mice. Anti-IL-10R treatment in vivo demonstrated that IL-10 was functional in determining vaccine failure, rendering LACK protective in the presence of high IFN-γ/low IL-5 responses.

Ubiquitin Conjugation of Open Reading Frame F DNA Vaccine Leads to Enhanced Cell-Mediated Immune Response and Induces Protection against Both Antimony-Susceptible and -Resistant Strains ofLeishmania donovani

“…Enhanced levels of these two cytokines may have a synergistic role in killing the parasite. It has been reported recently that IL-10 plays a suppressive role in parasite infection and dictates the susceptibility of L. donovani infection and is required for high parasite persistence in both C57BL/6 and susceptible BALB/c mice (68,69). Accordingly, the present data support this because we observed low levels of IL-10 in pUMVC3-UB-ORFF DNA-immunized and AG83-and GE1F8R-challenged mice when compared with the saline-or blank vector-infected mice.…”

Interleukin-10 from T Cells, but Not Macrophages and Granulocytes, Is Required for Chronic Disease in Leishmania mexicana Infection

“…However, because macrophages express Fc␥RI as well as Fc␥RIII and secrete IL-10 in response to IgG1 and IgG2a/c, there was circumstantial evidence that cells other than macrophages might be responsible for the critical IL-10 production that suppresses a needed Th1 response. In addition, IL-10 from T cells has important roles in other Leishmania infections (18)(19)(20)(21)(22). I have now presented direct data showing that T cell IL-10, but not macrophage (or granulocyte) IL-10, is required for chronic disease in murine L. mexicana infection.…”

Th1 and Th2 Cytokines Activity during Transformation and Lymphoma Formation Stage in Chicken Naturally Infected with Marek's disease virus.

“…Over expression of IL-10 may explain the increased severity of pathological pictures induced by MDV of high virulence. IL-10 leads to down regulation of immune response (Th1 responses) to intracellular pathogens (Stober et al, 2005) and its production is associated also with parasites persistence (Belkaid et al, 2001;Belkaid et al, 2002) and vaccine failure (Stober et al, 2005). IFN-γ expression is inversely proportional to IL-10 production, as IL-10 inhibits IFN-γ production in chickens (Rothwell et al, 2004).…”