Key Points
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Cutaneous leishmaniasis exhibits a wide spectrum of clinical presentations that is determined largely by the host immune response. The host immune response to infection is influenced both by host genetics and the Leishmania spp. and/or strain.
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The rapid recruitment of neutrophils and inflammatory monocytes following infection with Leishmania influences the course of disease. Neutrophils can have both protective and deleterious roles, whereas inflammatory monocytes kill Leishmania parasites and differentiate into monocyte-derived dendritic cells that promote the development of protective CD4+ T helper 1 (TH1) cells.
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Control of Leishmania infection depends on the production of interferon-γ by CD4+ TH1 cells, which leads to enhanced killing by macrophages due to the production of reactive oxygen species and nitric oxide.
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CD8+ T cells recruited to Leishmania lesions exhibit a cytolytic profile and lyse infected cells without killing the parasites, which leads to enhanced inflammation and increased severity of disease. Controlling these pathogenic CD8+ T cells, or the downstream mediators of inflammation that they induce, is a new approach to leishmaniasis immunotherapy.
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Infection with Leishmania generates several types of CD4+ T cells that mediate resistance to reinfection, including effector T cells, effector memory T cells, central memory T cells and tissue-resident memory T cells. There is currently no Leishmania vaccine, and a hurdle for vaccine development is that the most effective T cells are short-lived effector T cells; targeting longer lived central memory and tissue-resident memory T cells is an alternative approach.
Abstract
Cutaneous leishmaniasis is a major public health problem and causes a range of diseases from self-healing infections to chronic disfiguring disease. Currently, there is no vaccine for leishmaniasis, and drug therapy is often ineffective. Since the discovery of CD4+ T helper 1 (TH1) cells and TH2 cells 30 years ago, studies of cutaneous leishmaniasis in mice have answered basic immunological questions concerning the development and maintenance of CD4+ T cell subsets. However, new strategies for controlling the human disease have not been forthcoming. Nevertheless, advances in our knowledge of the cells that participate in protection against Leishmania infection and the cells that mediate increased pathology have highlighted new approaches for vaccine development and immunotherapy. In this Review, we discuss the early events associated with infection, the CD4+ T cells that mediate protective immunity and the pathological role that CD8+ T cells can have in cutaneous leishmaniasis.
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Acknowledgements
The authors thank L. King for critical reading of the manuscript and acknowledge financial support from the US National Institutes of Health (RO1 AI 106842; UO1 AI 088650; RO1 AI 125126).
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Supplementary information S1 (movie)
CD8+ T cell killing a Leishmania-infected target cell. Live cell imaging using a spinning disc confocal microscope of cells isolated from leishmanial lesions in Rag−/− mice infected with mCherry (red)-expressing Leishmania braziliensis and reconstituted with eGFP (green) CD8+ T cells 4 weeks post infection. This movie is reproduced with permission from PLoS Pathogens (Novais, F. O. et al. 9, e1003504 (2013)). (AVI 1102 kb)
Glossary
- Delayed-type hypersensitivity
-
(DTH). An inflammatory response that develops 48–72 h after injection of antigen into the skin. DTH indicates that an individual has a population of T cells that make interferon-γ and recognize that antigen.
- Respiratory burst
-
The rapid release of reactive oxygen species from immune cells during phagocytosis.
- CC-chemokine receptor 2
-
(CCR2). A receptor that binds monocyte chemoattractant protein (CCL2) and is involved in monocyte migration from the bone marrow to inflammatory sites.
- Reactive oxygen species
-
(ROS). Chemically reactive molecules that contain oxygen, and include superoxide anions, hydroxyl radicals and hydrogen peroxide.
- Nitric oxide
-
(NO). A free radical that is a gas that performs several biological functions and is involved in killing pathogens by macrophages.
- IL-12
-
A heterodimeric cytokine containing an IL-12p35 and an IL-12p40 chain that stimulates the production of interferon-γ from cells. IL-12 is crucial for the differentiation of CD4+ T helper 1 cells.
- Perforin
-
A calcium-sensitive membranolytic protein that is found in cytoplasmic granules of cytotoxic T lymphocytes and natural killer cells.
- NKG2D
-
(Natural killer group 2, member D). A protein expressed on the surface of activated natural killer and CD8+ T cells that binds to self-ligands that are induced following stress, development of malignancy and infection. Interactions between NKG2D and its ligands can induce lysis of the NKG2D ligand-expressing cell.
- Inflammasome
-
An innate immune sensor that recognizes pathogens and self molecules released during tissue damage. It is a molecular complex of several proteins; once assembled, the inflammasome processes pro-interleukin-1 (pro-IL-1) and pro-IL-18 to their active forms.
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Scott, P., Novais, F. Cutaneous leishmaniasis: immune responses in protection and pathogenesis. Nat Rev Immunol 16, 581–592 (2016). https://doi.org/10.1038/nri.2016.72
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DOI: https://doi.org/10.1038/nri.2016.72
