Beate Lorenz

Immune Modulating Effects of NKT Cells in a Physiologically Low Dose Leishmania major Infection Model after αGalCer Analog PBS57 Stimulation

Leishmaniasis is a parasitic infection affecting ∼12 million people worldwide, mostly in developing countries. Treatment options are limited and no effective vaccines exist to date. Natural Killer T (NKT) cells are a conserved innate-like lymphocyte population with immunomodulating effects in various settings. A number of reports state a role of NKT cells in different models of Leishmania infection. Here, we investigated the effect of NKT cells in a physiologically relevant, intradermal low dose infection model. After inoculation of 103 infectious-stage L. major, comparable numbers of skin-immigrating NKT cells in both susceptible BALB/c mice and resistant C57BL/6 mice were noted. Compared to their wild type counterparts, NKT cell-deficient mice on a C57BL/6 background were better able to contain infection with L. major and showed decreased IL-4 production in cytokine analysis performed 5 and 8 weeks after infection. Low doses of the NKT cell stimulating αGalCer analog PBS57 applied at the time of infection led to disease exacerbation in C57BL/6 wild-type, but not NKT-deficient mice. The effect was dependent both on the timing and amount of PBS57 administered. The effect of NKT cell stimulation by PBS57 proved to be IL-4 dependent, as it was neutralized in IL-4-deficient C57BL/6 or anti-IL-4 antibody-treated wild-type mice. In contrast to C57BL/6 mice, administration of PBS57 in susceptible BALB/c mice resulted in an improved course of disease. Our results reveal a strain- and cytokine-dependent regulatory role of NKT cells in the development of immunity to low dose L. major infections. These effects, probably masked in previous studies using higher parasite inocula, should be considered in future therapy and immunization approaches.

Disease control in cutaneous leishmaniasis is independent of IL-22.

University Hospital, Sousse, Tunisia; Department of Dermatology and Venerology, Nabeul Regional Hospital, Nabeul, Tunisia; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA; École Pratique des Hautes Études, heSam University and Institut du Cerveau et de la Moelle Epinière, Sorbonne University, PitiéSalpêtrière Hospital, Paris, France; Department of Pathological Anatomy and Cytology, Farhat Hached University Hospital, Sousse, Tunisia and Department of Paediatrics, National University of Singapore, Singapore, Singapore E-mail: ali.saad@rns.tn or bruno@reversade.com

IL-10 signaling in dendritic cells attenuates anti-Leishmania major immunity without affecting protective memory responses

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Isolation of T cells from the skin.

T cells can be found in skin under steady-state conditions as well as in inflammatory processes. T cells in skin play an important role in immune homeostasis as well as control of infectious, inflammatory diseases or tumors. In addition, several important and frequent skin diseases such as psoriasis, atopic dermatitis, autoimmune disease, and contact allergy are initiated by T cells. In skin diseases, the majority of antigen-specific T cells can be found in the tissue, not the peripheral blood. Here, we present a protocol suitable for isolation of skin-resident (inflammatory) T cells that can be used for an in-depth characterization of their frequency, function, and role for the respective inflammatory condition.

Topical treatment with a two-component gel releasing nitric oxide cures C57BL/6 mice from cutaneous leishmaniasis caused by Leishmania major.

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Insufficient generation of Th17 cells in IL‐23p19‐deficient BALB/c mice protects against progressive cutaneous leishmaniasis

Healing of leishmaniasis—a parasitic skin disease—is associated with high levels of secreted interferon (IFN)γ and IL‐12 in resistant C57BL/6 mice and humans. Susceptible BALB/c mice predominantly react with a Th17/Th2/Treg‐related immune response and finally succumb to infection. Previously, we showed that BALB/c IL‐17A−/− mice are protected against Leishmania (L.) major infections, indicating that IL‐17A—predominantly produced by Th17 cells—plays an important role for disease outcome. We now investigated DC‐derived cytokines and finally identified IL‐23p19 as key cytokine responsible for induction of Leishmania‐specific Th17 cells that play an important role for progressive disease in susceptible BALB/c mice.

Myeloid cells do not contribute to gender-dependent differences in disease outcome in murine cutaneous leishmaniasis.

Gender-associated differences in the outcome of infections are well known. Apart from behavior-released differences in their incidence, immunological factors also contribute to disease outcome. The underlying mechanisms are often unknown. Here, we show that in murine experimental leishmaniasis, female mice develop larger skin lesions that harbor significantly more parasites, exhibit increased parasite dissemination to visceral organs associated with a shift towards T helper (Th) 2 immunity with increased levels of IL-4. Antigen presenting cells (APC) responsible for T cell priming, such as macrophages or dendritic cells, were not involved in the process. Additionally, in adoptive transfer experiments, we show that differences in the lymphoid lineage are also not critical for mediating these gender-dependent effects. In summary, neither myeloid nor lymphoid cells contribute to disease outcome against this important human pathogen, but stromal cells influenced by e.g. hormonal effects in addition to other parts of the immune system might play a role.