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The Journal of Immunology, 2005, 175: 2517-2524.
Copyright © 2005 by The American Association of Immunologists

IL-10 from Regulatory T Cells Determines Vaccine Efficacy in Murine Leishmania major Infection1

Carmel B. Stober*,{dagger}, Uta G. Lange*,{dagger}, Mark T. M. Roberts*,{dagger}, Antonio Alcami{dagger} and Jenefer M. Blackwell2,*,{dagger}

* Cambridge Institute for Medical Research, University of Cambridge, and {dagger} Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom

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.




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