Distinct roles for IL‐6 and IL‐12p40 in mediating protection against Leishmania donovani and the expansion of IL‐10+ CD4+ T cells

Stäger, Simona; Maroof, Asher; Zubairi, Soombul; Sanos, Stéphanie L.; Köpf, Manfred; Kaye, Paul M.

doi:10.1002/eji.200635937

Cited by 118 publications

(155 citation statements)

References 48 publications

(59 reference statements)

Supporting

Mentioning

123

Contrasting

Unclassified

Order By: Relevance

“…In our system, transfer of DC primed with CpG was able to confer protection to IL-6 -/-susceptible mice, indicating that in our vaccine DC are crucial in initiating protective responses after vaccination with Lm + CpG. This finding reinforces what has been recently published by Stager et al in mice infected with L. donovani [42]. These authors found that transfer of BMDDC activated with LPS reduced parasite burden and blocked the expansion of IL-10-secreting CD4 + T cells in the visceral leishmaniasis model.…”

Section: Discussionsupporting

confidence: 90%

Immunomodulatory effects associated with a live vaccine against Leishmania major containing CpG oligodeoxynucleotides

Weigand

Belkaid

et al. 2006

Eur J Immunol

View full text Add to dashboard Cite

The inoculation of live Leishmania major to produce a lesion that heals (leishmanization) is to date the only vaccine against cutaneous leishmaniasis that has proven effective in humans, but it still has an unacceptable frequency of large ulcerating lesions that are slow to heal or, in rare cases, non-healing. We have previously shown that C57BL/6 mice vaccinated intradermally with 10 4 L. major/50 lg CpG oligodeoxynucleotides develop little or no dermal lesions and show early containment of parasite growth in the vaccination site, eliminating safety concerns related to the inoculation of live organisms. The addition of CpG to the live vaccine resulted in early activation of dermal dendritic cells and increased IL-6 production, as well as in a reduction in the accumulation of Foxp3 + CD4 + CD25 + regulatory T (T reg ) cells that naturally occurs in the skin following Leishmania infection. Neutralization of IL-6 caused the development of larger lesions and increased local T reg cell numbers. Transfer of vaccine-primed dendritic cells into IL-6-deficient mice mitigated lesion development, indicating that IL-6 reconstitution limited pathology in the vaccination site.

show abstract

Section: Discussionsupporting

confidence: 90%

Immunomodulatory effects associated with a live vaccine against Leishmania major containing CpG oligodeoxynucleotides

Weigand

Belkaid

et al. 2006

Eur J Immunol

View full text Add to dashboard Cite

show abstract

“…For example, increased expression of interleukin-10 during chronic L. donovani infection 32 may aid in limiting any toxic shock response. 33 On the other hand, although increased local interferon-␥ and tumor necrosis factor-␣ may enhance macrophage bactericidal activity, the threshold of macrophage activation remains below that necessary to achieve anti-leishmanial effects.…”

Section: Discussionmentioning

confidence: 99%

SIGNR1-Negative Red Pulp Macrophages Protect against Acute Streptococcal Sepsis after Leishmania donovani-Induced Loss of Marginal Zone Macrophages

Kirby

Beattie

Maroof

et al. 2009

The American Journal of Pathology

Self Cite

View full text Add to dashboard Cite

Marginal zone macrophages in the murine spleen play an important role in the capture of blood-borne pathogens and are viewed as an essential component of host defense against the development of pneumococcal sepsis. However, we and others have previously described the loss of marginal zone macrophages associated with the splenomegaly that follows a variety of viral and protozoal infections; this finding raises the question of whether these infected mice would become more susceptible to secondary pneumococcal infection. Contrary to expectations, we found that mice lacking marginal zone macrophages resulting from Leishmania donovani infection have increased resistance to Streptococcus pneumoniae type 3 and do not develop sepsis. Using biophotonic imaging, we observed that pneumococci are rapidly trapped in the spleens of L. donovani-infected mice. By selective depletion studies using clodronate liposomes, depleting monoclonal antibodies specific for Ly6C/G and Ly6G, and CD11c-DTR mice, we show that the enhanced early resistance in L. donovani-infected mice is entirely due to the activity of SIGNR1 ؊ red pulp macrophages. Our data demonstrate, therefore, that the normal requirement for SIGNR1 ؉ marginal zone macrophages to protect against a primary pneumococcal infection can, under conditions of splenomegaly, be readily compensated for by activated red pulp macrophages.

show abstract

“…Ϫ Foxp3 Ϫ cells in L. donovani infection (54). Because BALB/c and IL-4R␣ Ϫ/Ϫ mice have similar parasite loads ( Fig.…”

Section: Cd25mentioning

confidence: 98%

Despite Increased CD4+Foxp3+ Cells within the Infection Site, BALB/c IL-4 Receptor-Deficient Mice Reveal CD4+Foxp3-Negative T Cells as a Source of IL-10 inLeishmania majorSusceptibility

Nagase

Jones

Anderson

et al. 2007

The Journal of Immunology

View full text Add to dashboard Cite

BALB/c IL-4Rα−/− mice, despite the absence of IL-4/IL-13 signaling and potent Th2 responses, remain highly susceptible to Leishmania major substain LV39 due exclusively to residual levels of IL-10. To address the contribution of CD4+CD25+ T regulatory (Treg) cells to IL-10-mediated susceptibility, we depleted CD4+CD25+ cells in vivo and reconstituted IL-4Rα × RAG2 recipients with purified CD4+CD25− T cells. Although anti-CD25 mAb treatment significantly decreased parasite numbers in IL-4Rα−/− mice, treatment with anti-IL-10R mAb virtually eliminated L. major parasites in both footpad and dermal infection sites. In addition, IL-4Rα × RAG2 mice reconstituted with CD4+ cells depleted of CD25+ Treg cells remained highly susceptible to infection. Analysis of L. major-infected BALB/c and IL-4Rα−/− inflammatory sites revealed that the majority of IL-10 was secreted by the CD4+Foxp3− population, with a fraction of IL-10 coming from CD4+Foxp3+ Treg cells. All T cell IFN-γ production was also derived from the CD4+Foxp3− population. Nevertheless, the IL-4Rα−/−-infected ear dermis, but not draining lymph nodes, consistently displayed 1.5- to 2-fold greater percentages of CD4+CD25+ and CD4+Foxp3+ Treg cells compared with the BALB/c-infected dermis. Thus, CD4+Foxp3− T cells are a major source of IL-10 that disrupts IFN-γ activity in L. major-susceptible BALB/c mice. However, the increase in CD4+Foxp3+ T cells within the IL-4Rα−/− dermis implies a possible IL-10-independent role for Treg cells within the infection site, and may indicate a novel immune escape mechanism used by L. major parasites in the absence of IL-4/IL-13 signaling.

show abstract

Distinct roles for IL‐6 and IL‐12p40 in mediating protection against Leishmania donovani and the expansion of IL‐10⁺ CD4⁺ T cells

Cited by 118 publications

References 48 publications

Immunomodulatory effects associated with a live vaccine against Leishmania major containing CpG oligodeoxynucleotides

Immunomodulatory effects associated with a live vaccine against Leishmania major containing CpG oligodeoxynucleotides

SIGNR1-Negative Red Pulp Macrophages Protect against Acute Streptococcal Sepsis after Leishmania donovani-Induced Loss of Marginal Zone Macrophages

Despite Increased CD4+Foxp3+ Cells within the Infection Site, BALB/c IL-4 Receptor-Deficient Mice Reveal CD4+Foxp3-Negative T Cells as a Source of IL-10 inLeishmania majorSusceptibility

Contact Info

Product

Resources

About