Dendritic Cell-Mediated Vaccination Relies on Interleukin-4 Receptor Signaling to Avoid Tissue Damage after Leishmania major Infection of BALB/c Mice

Anita Masic,Ramona Hurdayal,Frank Brombacher,Natalie E Nieuwenhuizen,Heidrun Moll,Genevieve Milon

doi:10.1371/journal.pntd.0001721

Anita Masic, Ramona Hurdayal + Show 4 more

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https://doi.org/10.1371/journal.pntd.0001721

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Abstract

Prevention of tissue damages at the site of Leishmania major inoculation can be achieved if the BALB/c mice are systemically given L. major antigen (LmAg)-loaded bone marrow-derived dendritic cells (DC) that had been exposed to CpG-containing oligodeoxynucleotides (CpG ODN). As previous studies allowed establishing that interleukin-4 (IL-4) is involved in the redirection of the immune response towards a type 1 profile, we were interested in further exploring the role of IL-4. Thus, wild-type (wt) BALB/c mice or DC-specific IL-4 receptor alpha (IL-4Rα)-deficient (CD11ccreIL-4Rα−/lox) BALB/c mice were given either wt or IL-4Rα-deficient LmAg-loaded bone marrow-derived DC exposed or not to CpG ODN prior to inoculation of 2×105 stationary-phase L. major promastigotes into the BALB/c footpad. The results provide evidence that IL4/IL-4Rα-mediated signaling in the vaccinating DC is required to prevent tissue damage at the site of L. major inoculation, as properly conditioned wt DC but not IL-4Rα-deficient DC were able to confer resistance. Furthermore, uncontrolled L. major population size expansion was observed in the footpad and the footpad draining lymph nodes of CD11ccreIL-4Rα−/lox mice immunized with CpG ODN-exposed LmAg-loaded IL-4Rα-deficient DC, indicating the influence of IL-4Rα-mediated signaling in host DC to control parasite replication. In addition, no footpad damage occurred in BALB/c mice that were systemically immunized with LmAg-loaded wt DC doubly exposed to CpG ODN and recombinant IL-4. We discuss these findings and suggest that the IL4/IL4Rα signaling pathway could be a key pathway to trigger when designing vaccines aimed to prevent damaging processes in tissues hosting intracellular microorganisms.

Highlights

Leishmania spp. infection in experimental mouse models provided insights into the polarization of immune responses against intracellular parasites, resulting either in self-healing local inflammation (e.g., C57BL/6) or severe and fatal leishmaniasis (e.g., BALB/c) [1,2]
In the present study we investigated the role of IL-4 receptor alpha (IL-4Ra)-mediated instruction of the vaccinating Dendritic cells (DC) and the host DC during induction of protection against leishmaniasis
The results demonstrate that IL-4Ra signaling in DC used as vaccine carrier plays an important role in induction of protective immunity against L. major infection, as only mice vaccinated with IL-4 responder DC are able to trigger effective Th1-mediated immunity

Summary

Introduction

Leishmania spp. infection in experimental mouse models provided insights into the polarization of immune responses against intracellular parasites, resulting either in self-healing local inflammation (e.g., C57BL/6) or severe and fatal leishmaniasis (e.g., BALB/c) [1,2]. BALB/c mice fail to develop a protective interferon (IFN)-c-mediated T helper (Th) 1 response to Leishmania infection [3,4], but show a disease-promoting IL-4-driven Th2 response [5,6]. We previously demonstrated that the Toll-like receptor (TLR) 9 ligand CpG oligodeoxynucleotides (ODN) is a potent inducer of DC-derived IL-12, enabling DC to mediate complete and long-lasting immunity to experimental leishmaniasis. Prophylactic immunization with CpG ODN-activated and Leishmania major antigen (LmAg)-loaded BMDC one week or even 16 weeks prior to challenge has been shown to confer protection against L. major and, these cured mice resist a secondary challenge 10 weeks after primary infection showing no sign of disease up to 20 weeks after rechallenge [12]. Protection was not dependent on IL-12 secretion by the immunizing DC, as BALB/c mice treated with LmAg-loaded IL-12p352/2 or IL-12p402/2 DC were resistant against L. major infection, but the availability of recipient IL-12 was essential for the initiation of a protective immune response by DC, as neutralization of IL-12 during T cell priming diminished the protective effect of the vaccine [12]

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