0000000000190174
AUTHOR
Mark C. Udey
Requirements for Th1-dependent immunity against infection with Leishmania major
Protective immunity against cutaneous leishmaniasis is dependent on the induction of Th1/Tc1 immune responses resulting in efficient parasite elimination. In this review, the mechanisms leading to protection are discussed with special focus on the role of Leishmania major-infected dendritic cells (DC) in induction of Th1-dependent immunity. Murine strain-dependent differences between DC derived from Leishmania-susceptible as compared to resistant mice are highlighted.
Skin-derived macrophages from Leishmania major-susceptible mice exhibit interleukin-12- and interferon-gamma-independent nitric oxide production and parasite killing after treatment with immunostimulatory DNA.
Co-administration of CpG-containing immunostimulatory oligodeoxynucleotides and parasite antigen protects susceptible BALB/c mice from otherwise progressive infection with Leishmania major. Although the protective effect of CpG-containing immunostimulatory oligodeoxynucleotides is clearly dependent on endogenous interleukin-12 and interferon-gamma production, the source of these Th1-promoting cytokines in infected mice is unknown. In contrast to macrophages from Leishmania-resistant C57BL/6 mice, macrophages from susceptible BALB/c mice are hyporesponsive to stimulation with lipopolysaccharide and interferon-gamma. While studying interactions of various antigen-presenting cells with Leishma…
Distinct Roles for IL-1 Receptor Type I Signaling in Early Versus Established Leishmania major Infections
IL-1alpha/beta released by infected dendritic cells (DC) plays a critical role in the development of protective immunity against Leishmania major. Previous studies demonstrated that treatment of susceptible BALB/c mice with IL-1alpha during T-cell priming (days 1-3 post-infection) induced T helper (Th)1-mediated protection. In contrast, we now demonstrate that prolonged treatment with IL-1alpha (for 3 weeks) worsened disease outcome. To characterize the receptor involved, L. major infections in IL-1 receptor type I (IL-1RI) knockout mice were studied. In C57BL/6 IL-1RI-/- mice, the IL-1alpha-mediated protective effect was abrogated. The course of high-dose infection (2 x 10(5) parasites) in…
Dendritic cell-derived IL-12p40 homodimer contributes to susceptibility in cutaneous leishmaniasis in BALB/c mice
Abstract Protection against Leishmania major in resistant C57BL/6 mice is mediated by Th1 cells, whereas susceptibility in BALB/c mice is the result of Th2 development. IL-12 release by L. major-infected dendritic cells (DC) is critically involved in differentiation of Th1 cells. Previously, we reported that strain differences in the production of DC-derived factors, e.g., IL-1αβ, are in part responsible for disparate disease outcome. In the present study, we analyzed the release of IL-12 from DC in more detail. Stimulated DC from C57BL/6 and BALB/c mice released comparable amounts of IL-12p40 and p70. In the absence of IL-4, BALB/c DC produced significantly more IL-12p40 than C57BL/6 DC. D…
Skin Dendritic Cells in Murine Cutaneous Leishmaniasis
Studies of the immunopathogenesis of Leishmania major-induced murine cutaneous leishmaniasis provide a framework for understanding the evolution of L. major infection of skin in humans and the foundation for rationale vaccine design. Experiments in which infection is initiated with "suprap hysiologic" numbers of parasites clearly identify Th-derived type I cytokines as essential participants in macrophage activation and macrophage nitric oxide production as prerequisite for parasite control. Dendritic cells, rather than macrophages, appear to be responsible for L. major-specific Th priming in these studies. Recent studies of murine cutaneous leishmaniasis in a model system in which infectio…
Leishmania major-infected murine Langerhans cell-like dendritic cells from susceptible mice release IL-12 after infection and vaccinate against experimental cutaneous Leishmaniasis
Leishmania major-infected C57BL / 6 skin-dendritic cells (DC) are activated and release cytokines (including IL-12 p70), and likely initiate protective Th1 immunity in vivo (von Stebut, E. et al., J. Exp. Med.188: 1547 – 1552). To characterize differences in DC function in mice that are genetically susceptible (BALB / c) and resistant (C57BL / 6) to cutaneous leishmaniasis, we analyzed the effects of L. major on Langerhans cell-like, fetal skin-derived DC (FSDDC) from both strains. BALB / c- and C57BL / 6-FSDDC ingested similar numbers of amastigotes, but did not ingest metacyclic promastigotes. Like C57BL / 6-FSDDC, infection of BALB / c-FSDDC led to up-regulation of MHC class I and II ant…
Uptake of Leishmania major by dendritic cells is mediated by Fcγ receptors and facilitates acquisition of protective immunity
Uptake of Leishmania major by dendritic cells (DCs) results in activation and interleukin (IL)-12 release. Infected DCs efficiently stimulate CD4- and CD8- T cells and vaccinate against leishmaniasis. In contrast, complement receptor 3-dependent phagocytosis of L. major by macrophages (MPhi) leads exclusively to MHC class II-restricted antigen presentation to primed, but not naive, T cells, and no IL-12 production. Herein, we demonstrate that uptake of L. major by DCs required parasite-reactive immunoglobulin (Ig)G and involved FcgammaRI and FcgammaRIII. In vivo, DC infiltration of L. major-infected skin lesions coincided with the appearance of antibodies in sera. Skin of infected B cell-de…
IL-1 signalling is dispensable for protective immunity in Leishmania-resistant mice
Leishmaniasis is a parasitic disease affecting ∼12 million people. Control of infection (e.g. in C57BL/6 mice) results from IL-12-dependent production of IFNγ by Th1/Tc1 cells. In contrast, BALB/c mice succumb to infection because of preferential Th2-type cytokine induction. Infected dendritic cells (DC) represent important sources of IL-12. Genetically determined differences in DC IL-1α/β production contribute to disease outcome. Whereas the course of disease was not dramatically altered in IL-1RI(-/-) mice, local administration of IL-1α to infected C57BL/6 mice improved disease outcome. To definitively elucidate the involvement of IL-1 in immunity against leishmaniasis, we now utilized IL…
Interleukin 1α Promotes Th1 Differentiation and Inhibits Disease Progression in Leishmania major–susceptible BALB/c Mice
Protective immunity against pathogens such as Leishmania major is mediated by interleukin (IL)-12–dependent Th1-immunity. We have shown previously that skin-dendritic cells (DCs) from both resistant C57BL/6 and susceptible BALB/c mice release IL-12 when infected with L. major, and infected BALB/c DCs effectively vaccinate against leishmaniasis. To determine if cytokines other than IL-12 might influence disease outcome, we surveyed DCs from both strains for production of a variety of cytokines. Skin-DCs produced significantly less IL-1α in response to lipopolysaccharide/interferon γ or L. major when expanded from BALB/c as compared with C57BL/6 mice. In addition, IL-1α mRNA accumulation in l…
A Role for Leukocyte-Derived IL-1RA in DC Homeostasis Revealed by Increased Susceptibility of IL-1RA-Deficient Mice to Cutaneous Leishmaniasis
Dendritic cell (DC)-derived IL-1α/β plays a critical role in the induction of T helper type 1 (Th1)-dependent immunity against Leishmania . DCs from susceptible BALB/c mice produce less IL-1α/β when compared with resistant C57BL/6 mice, contributing to aberrant Th2 development and ultimate death of infected mice. We have extended our studies of the role of IL-1 in leishmaniasis using IL-1RA -/- BALB/c mice that are characterized by upregulated IL-1 receptor signaling. Unexpectedly, infection of IL-1RA -/- mice led to significantly worsened disease outcome with larger lesions, dramatically higher parasite burdens, and decreased IFN-γ production by antigen-specific T cells. We determined that…
IL-17 promotes progression of cutaneous leishmaniasis in susceptible mice.
Abstract Resistance to leishmaniasis in C57BL/6 mice depends on Th1/Tc1 cells. BALB/c mice preferentially develop Th2 immunity and succumb to infection. We now assessed the role of IL-17 in cutaneous leishmaniasis. During the course of Leishmania major infection, BALB/c CD4 cells and neutrophils produced increased amounts of IL-17 as compared with cells from C57BL/6 mice. This increase was associated with significantly increased IL-23 release from L. major-infected BALB/c dendritic cells (DC), whereas IL-6 and TGF-β1 production by BALB/c and C57BL/6 DC were comparable. Interestingly, lesion sizes in infected IL-17-deficient BALB/c mice were dramatically smaller and failed to progress as com…
Vaccination with TAT-Antigen Fusion Protein Induces Protective, CD8+ T Cell-Mediated Immunity Against Leishmania Major
In murine leishmaniasis, healing is mediated by IFN-γ-producing CD4 + and CD8 + T cells. Thus, an efficacious vaccine should induce Th1 and Tc1 cells. Dendritic cells (DCs) pulsed with exogenous proteins primarily induce strong CD4-dependent immunity; induction of CD8 responses has proven to be difficult. We evaluated the immunogenicity of fusion proteins comprising the protein transduction domain of HIV-1 TAT and the Leishmania antigen LACK ( Leishmania homolog of receptors for activated C kinase), as TAT-fusion proteins facilitate major histocompatibility complex class I-dependent antigen presentation. In vitro , TAT–LACK-pulsed DCs induced stronger proliferation of Leishmania -specific C…