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

• Published in: The Journal of immunology (1950) 2005-08, Vol.175 (4), p.2517-2524
• Main Authors: Stober, Carmel B, Lange, Uta G, Roberts, Mark T. M, Alcami, Antonio, Blackwell, Jenefer M
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Protozoan - administration & dosage; Antigens, Protozoan - immunology; Female; Immunity, Active; Immunization, Secondary; Immunoglobulin G - biosynthesis; Interferon-gamma - biosynthesis; Interleukin-10 - biosynthesis; Interleukin-10 - metabolism; Interleukin-10 - physiology; Interleukin-4 - biosynthesis; Leishmania major - immunology; Leishmaniasis, Cutaneous - immunology; Leishmaniasis, Cutaneous - prevention & control; Mice; Mice, Inbred BALB C; Peroxidases - administration & dosage; Peroxidases - immunology; Predictive Value of Tests; Protozoan Proteins - administration & dosage; Protozoan Proteins - immunology; Protozoan Vaccines - administration & dosage; Protozoan Vaccines - immunology; Receptors, Interleukin-2 - biosynthesis; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Treatment Failure; Vaccines, DNA - administration & dosage; Vaccines, DNA - immunology; Vaccinia virus - genetics; Vaccinia virus - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.175.4.2517

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.