T Cell-Derived IL-10 Determines Leishmaniasis Disease Outcome and Is Suppressed by a Dendritic Cell Based Vaccine

Tobias Schwarz,Werner Müller,Katharina A Remer,Heidrun Moll,Wiebke Nahrendorf,Anita Masic,Lisa Siewe,Axel Roers,Ingrid Müller

doi:10.1371/journal.ppat.1003476

Abstract

In the murine model of Leishmania major infection, resistance or susceptibility to the parasite has been associated with the development of a Th1 or Th2 type of immune response. Recently, however, the immunosuppressive effects of IL-10 have been ascribed a crucial role in the development of the different clinical correlates of Leishmania infection in humans. Since T cells and professional APC are important cellular sources of IL-10, we compared leishmaniasis disease progression in T cell-specific, macrophage/neutrophil-specific and complete IL-10-deficient C57BL/6 as well as T cell-specific and complete IL-10-deficient BALB/c mice. As early as two weeks after infection of these mice with L. major, T cell-specific and complete IL-10-deficient animals showed significantly increased lesion development accompanied by a markedly elevated secretion of IFN-γ or IFN-γ and IL-4 in the lymph nodes draining the lesions of the C57BL/6 or BALB/c mutants, respectively. In contrast, macrophage/neutrophil-specific IL-10-deficient C57BL/6 mice did not show any altered phenotype. During the further course of disease, the T cell-specific as well as the complete IL-10-deficient BALB/c mice were able to control the infection. Furthermore, a dendritic cell-based vaccination against leishmaniasis efficiently suppresses the early secretion of IL-10, thus contributing to the control of parasite spread. Taken together, IL-10 secretion by T cells has an influence on immune activation early after infection and is sufficient to render BALB/c mice susceptible to an uncontrolled Leishmania major infection.

Highlights

Infection with intracellular protozoan parasites of the genus Leishmania leads to a broad range of disease manifestations in humans, ranging from an asymptomatic carrier status or localized, self-healing cutaneous leishmaniasis to disseminating visceral disease [1]
Using T cell-specific and macrophage-specific mutant mice, we demonstrate that abrogating the secretion of the immunosuppressive cytokine IL-10 by T cells is sufficient to render otherwise susceptible mice resistant to an infection with the pathogen
The healing phenotype is accompanied by an elevated specific inflammatory immune response very early after infection

Summary

Introduction

Infection with intracellular protozoan parasites of the genus Leishmania leads to a broad range of disease manifestations in humans, ranging from an asymptomatic carrier status or localized, self-healing cutaneous leishmaniasis to disseminating visceral disease (kala azar) [1]. The outcome of infection depends on the parasite species, but is influenced by the host immune response [2,3]. In naturally resistant mouse strains such as C57BL/6 or C3H, IL-12, secreted mainly by dendritic cells (DC), has the essential role of inducing a Th1 immune response. IL-42/2 BALB/c mice are able to control infection with some Leishmania major strains at least partially [4] and BALB/c mice treated with anti-IL-4 Ab at the time of challenge exhibit a healing phenotype [5]. There is convincing evidence that the early IL-4 response is confined largely to an oligoclonal population of CD4+ T cells with a

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