title: 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-gamma 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-gamma 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-gamma:IL-10 was thus a clear prechallenge indicator of vaccine success. Challenge infection caused further polarization to high IL-10/low IFN-gamma with LACK and low IL-10/high IFN-gamma 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-gamma/low IL-5 responses.
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, United Kingdom.
authors.forename: Carmel B
authors.initials: CB
authors.lastname: Stober
authors.forename: Uta G
authors.initials: UG
authors.lastname: Lange
authors.forename: Mark T M
authors.initials: MT
authors.lastname: Roberts
authors.forename: Antonio
authors.initials: A
authors.lastname: Alcami
authors.forename: Jenefer M
authors.initials: JM
authors.lastname: Blackwell
mesh_terms: D000818:Animals; D000953:Antigens, Protozoan / Q000008:administration & dosage / Q000276:immunology; D005260:Female; D007110:Immunity, Active; D007117:Immunization, Secondary; D007074:Immunoglobulin G / Q000096:biosynthesis; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D015847:Interleukin-4 / Q000096:biosynthesis; D018320:Leishmania major / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology* / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D010544:Peroxidases / Q000008:administration & dosage / Q000276:immunology; D011237:Predictive Value of Tests; D015800:Protozoan Proteins / Q000008:administration & dosage / Q000276:immunology; D016052:Protozoan Vaccines / Q000008:administration & dosage / Q000276:immunology*; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D017211:Treatment Failure; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology
chemical_list: D000953:Antigens, Protozoan; D007074:Immunoglobulin G; D015800:Protozoan Proteins; D016052:Protozoan Vaccines; D015375:Receptors, Interleukin-2; D019444:Vaccines, DNA; D016753:Interleukin-10; C093139:LACK antigen, Leishmania; D015847:Interleukin-4; D007371:Interferon-gamma; D010544:Peroxidases; C110959:tryparedoxin peroxidase