LeishmaniaPriming of Human Dendritic Cells for CD40 Ligand-Induced Interleukin-12p70 Secretion Is Strain and Species Dependent

Abstract

A major question in the study of leishmaniasis is what dictates clinical disease expression produced by different Leishmania species, i.e., cutaneous versus systemic and healing versus nonhealing. Animal models using a Leishmania species associated with self-limiting cutaneous disease (L. major) have revealed that protective immunity requires CD40/CD40 ligand (CD40L)-dependent, interleukin-12 (IL-12)-driven Th1 responses. We recently showed that L. major can prime human dendritic cells (DCs) for CD40L-triggered IL12p70 secretion and that these cells can drive a Th1 response in autologous T cells from sensitized individuals. Here we show that in contrast to L. major, Leishmania species responsible for visceral disease (L. donovani), as well as species associated with persistent, cutaneous lesions and occasional systemic disease (L. tropica), did not induce CD40L-dependent IL-12p70 production, despite comparable levels of uptake by DCs. Up-regulated surface expression of CD40 did not correlate with IL-12p70 production, and appreciable CD40L-induced IL-12p40 secretion was observed in uninfected as well as infected DCs, regardless of species. Reverse transcription-PCR analysis confirmed that the production of heterodimeric IL-12 was limited by expression of IL-12p35 mRNA, which was dependent on both a microbial priming signal and CD40 engagement for its high-level induction. The intrinsic differences in the ability of Leishmania species to prime DCs for CD40L-dependent IL-12p70 secretion may account, at least in part, for the evolution of healing and nonhealing forms of leishmanial disease.Leishmaniasis is a vector-borne parasitic disease which, depending mainly upon the species of Leishmania, can display a spectrum of clinical manifestations ranging from localized cutaneous lesions that heal spontaneously to generalized systemic disease with fatal outcome. Regardless of species and clinical outcome, all Leishmania infections are initiated by infectious-stage metacyclic promastigotes which are deposited in the skin following a sand fly bite. These forms are taken up by macrophages and replicate as intracellular amastigotes. The pathology that is typical of localized cutaneous disease is immune mediated and is accompanied by the control of infection in the skin. In contrast, the absence of strong acquired immunity, while moderating the development of dermal pathology, results in parasite dissemination and uncontained parasite growth in liver, spleen,

TRANCE-RANK Costimulation is Required for IL-12 Production and the Initiation of a Th1-Type Response toLeishmania majorInfection in CD40L-Deficient Mice

“…This is evidenced by several observations showing that disruption of the CD40-CD40L costimulatory pathway reduces IL-12 production and reverses the normal healing pattern of an L. major infection in a resistant strain of mouse (21,22). In addition, recent studies have shown that infection-induced IL-12 production by Leishmania-infected DCs requires additional signaling through the CD40-CD40L pathway (20,19).…”

“…Still, direct infection is not always a sufficient stimulus to induce production of this cytokine as evidenced by the observation that infection of human myeloid DCs with L. major failed to directly induce IL-12 production, although infection did up-regulate levels of MHC class II and costimulatory molecules. However, following interaction with CD40 ligand, infected DCs did produce increased levels IL-12p70 over that produced by uninfected DCs (19) although the capacity to stimulate IL-12 production varied depending on the species or strain of Leishmania used to stimulate cells (20). The concept that CD40-CD40L interactions provide a necessary stimulus for IL-12 production during cutaneous leishmaniasis is strongly supported by in vivo studies showing that CD40 (21) and CD40L (22,23) deficient mice as well as mice treated with neutralizing anti-CD40L Ab (24) fail to develop a protective cell mediated immune response following infection with L. major and the related protozoan parasite, Leishmania amazonensis.…”

Transcriptional Inhibition of Interleukin-12 Promoter Activity in Leishmania Spp.–Infected Macrophages

“…infection is likely dendritic cells (Gorak et al, 1998;Marovich et al, 2000;McDowell et al, 2002). However, Leishmania spp.-infected dendritic cells require CD40L costimulation for IL-12 production (Marovich et al, 2000;McDowell et al, 2002), suggesting that during infection, dendritic cells initiate a protective response after interaction with antigenspecific T-cells in lymphoid tissue. For parasites that normally target MP for survival, the avoidance of IL-12 early during infection would serve as an adaptive strategy to establish an infection.…”

Production of IL-12 by Macrophages Infected withToxoplasma gondiiDepends on the Parasite Genotype

“…Infection by Leishmania tropica and Leishmania donovani results in nonhealing cutaneous and severe visceral forms of leishmaniasis, respectively. These two species are deficient in the ability to prime DCs for CD40L-dependent IL-12 production relative to Leishmania major, which causes a less severe form of cutaneous disease (34).…”