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 compared with those in control mice. Similar amounts of IL-4, IL-10, and IFN-γ were produced by T cells from IL-17-deficient mice and control mice consistent with development of Th2-predominant immunity in all animals. Improved disease outcome was associated with decreased CXCL2-accumulation in lesion sites and decreased neutrophil immigration into lesions of infected IL-17-deficient mice confirming prior observations that enhanced neutrophil recruitment contributes to disease susceptibility in BALB/c mice. This study excludes an important facilitating role for IL-17 in Th1/Th2 development in L. major-infected BALB/c mice, and suggests that IL-23 production by L. major-infected DC maintains IL-17+ cells that influence disease progression via regulation of neutrophil recruitment.

Langerhans cells suppress the immune response to low-dose Leishmania major infection in part by inducing regulatory T cells.

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 IFNc 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-1a ⁄ b production contribute to disease outcome. Whereas the course of disease was not dramatically altered in IL-1RI ) ⁄ ) mice, local administration of IL-1a to infected C57BL ⁄ 6 mice improved disease outcome. To definitively elucidate the involvement of IL-1 in immunity against leishmaniasis, we now utilized IL-1a ⁄ b-double-deficient C57BL ⁄ 6 mice. C57BL ⁄ 6 mice are believed to be a good surrogate model for human, self limited cutaneous leishmaniasis (CL). Leishmania major-infected IL-1a ⁄ b ) ⁄ ) mice were resistant to experimental CL comparable to controls. In addition, DC-based vaccination against leishmaniasis in C57BL ⁄ 6 mice was independent of IL-1. Thus, in Leishmania-resistant C57BL ⁄ 6 mice, IL-1 signalling is dispensable for protection.

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-1RA(-/-) DCs were more mature already in the steady state, exhibited less phagocytotic capacity, and IL-12 production in response to various stimuli was impaired. Our data suggest that in addition to effects on Th education, IL-1α/β signaling also modulates DC homeostasis with increased signaling, leading to downmodulation of IL-12 synthesis and worsened disease outcome after infection with Leishmania major. Thus, the complex regulation of various members of the IL-1 cytokine family mediated through effects on both DCs and T cells critically contributes to disease outcome against this important human pathogen.

Background: Using a T helper (Th)1/Th2 disease model, we previously showed that genetically determined Th development depends on dendritic cell-derived interleukin (IL)-1α. In Leishmania major infections, Th1 immunity develops if IL-1α is present during T cell priming, whereas at later time points, IL-1α worsens disease outcome. In the present study, we determined the role of IL-1α in other Th2-mediated diseases. Methods: BALB/c mice were subjected to delayed-type hypersensitivity (DTH) or ovalbumin (OVA)/alum-induced allergic asthma in the presence or absence of IL-1α. Results: In DTH, mice treated with IL-1α during sensitization with keyhole limpet hemocyanin (KLH)/alum developed decreased footpad swelling associated with elevated KLH-specific interferon-γ levels. In asthma, significantly decreased airway hypersensitivity responses (AHRs) were detected upon treatment with IL-1α during T cell priming. In contrast to control mice, IL-1α-treated mice showed reduced peribronchial inflammatory infiltrates. The bronchoalveolar lavage (BAL) fluid contained significantly decreased eosinophil numbers (approximately 50%), but 4 times more neutrophils. The BAL fluid of IL-1α-treated BALB/c exhibited reduced amounts of IL-5 and OVA-specific IgE serum levels. In contrast, IL-1α treatment at later time points after sensitization or during allergen challenge worsened AHR, had no effect on lung inflammation and BAL fluid cell composition. Furthermore, cytokine levels (IL-5, IL-13) and antigen-specific IgE were increased or unaltered under these conditions. Conclusion: Similarly to leishmaniasis, IL-1α administration during sensitization of Th2-mediated allergic reactions suppresses the course of disease by shifting the immune response towards Th1, whereas later treatments worsen disease outcome. Future studies will elucidate the therapeutic value of IL-1α in asthmatic patients.