Splenic CD4+ T Cells in Progressive Visceral Leishmaniasis Show a Mixed Effector-Regulatory Phenotype and Impair Macrophage Effector Function through Inhibitory Receptor Expression Article Swipe
Audrie A. Medina-Colorado
,
E. Yaneth Osorio
,
Ómar A. Saldarriaga
,
Bruno L. Travi
,
Fanping Kong
,
Heidi Spratt
,
Lynn Soong
,
Peter C. Melby
·
YOU?
·
· 2017
· Open Access
·
· DOI: https://doi.org/10.1371/journal.pone.0169496
YOU?
·
· 2017
· Open Access
·
· DOI: https://doi.org/10.1371/journal.pone.0169496
Visceral leishmaniasis (VL), caused by infection with the intracellular protozoan Leishmania donovani, is a chronic progressive disease with a relentlessly increasing parasite burden in the spleen, liver and bone marrow. The disease is characterized by fever, splenomegaly, cachexia, and pancytopenia, and progresses to death if not treated. Control of Leishmania infection is mediated by Th1 (IFNγ-producing) CD4+ T cells, which activate macrophages to produce nitric oxide and kill intracellular parasites. However, despite expansion of CD4+ T cells and increased IFNγ expression in the spleen, humans with active VL do not control the infection. We used an experimental model of chronic progressive VL in hamsters, which mimics clinical and pathological features seen in humans, to better understand the mechanisms that lead to progressive disease. Transcriptional profiling of the spleen during chronic infection revealed expression of markers of both T cell activation and inhibition. CD4+ T cells isolated from the spleen during chronic progressive VL showed mixed expression of Th1 and Th2 cytokines and chemokines, and were marginally effective in controlling infection in an ex vivo T cell-macrophage co-culture system. Splenic CD4+ T cells and macrophages from hamsters with VL showed increased expression of inhibitory receptors and their ligands, respectively. Blockade of the inhibitory receptor PD-L2 led to a significant decrease in parasite burden, revealing a pathogenic role for the PD-1 pathway in chronic VL. PD-L2 blockade was associated with a dramatic reduction in expression of host arginase 1, but no change in IFNγ and inducible nitric oxide synthase. Thus, the expression of counter-regulatory molecules on splenic CD4+ T cells and macrophages promotes a more permissive macrophage phenotype and attenuates intracellular parasite control in chronic progressive VL. Host-directed adjunctive therapy targeting the PD-1 regulatory pathway may be efficacious for VL.
Related Topics
Concepts
Biology
Immunology
Spleen
Visceral leishmaniasis
Leishmania donovani
Chemokine
Immune system
Leishmaniasis
Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1371/journal.pone.0169496
- https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0169496&type=printable
- OA Status
- gold
- Cited By
- 48
- References
- 61
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W2575081296
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W2575081296Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1371/journal.pone.0169496Digital Object Identifier
- Title
-
Splenic CD4+ T Cells in Progressive Visceral Leishmaniasis Show a Mixed Effector-Regulatory Phenotype and Impair Macrophage Effector Function through Inhibitory Receptor ExpressionWork title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2017Year of publication
- Publication date
-
2017-01-19Full publication date if available
- Authors
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Audrie A. Medina-Colorado, E. Yaneth Osorio, Ómar A. Saldarriaga, Bruno L. Travi, Fanping Kong, Heidi Spratt, Lynn Soong, Peter C. MelbyList of authors in order
- Landing page
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https://doi.org/10.1371/journal.pone.0169496Publisher landing page
- PDF URL
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https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0169496&type=printableDirect link to full text PDF
- Open access
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YesWhether a free full text is available
- OA status
-
goldOpen access status per OpenAlex
- OA URL
-
https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0169496&type=printableDirect OA link when available
- Concepts
-
Biology, Immunology, Spleen, Visceral leishmaniasis, Leishmania donovani, Chemokine, Immune system, LeishmaniasisTop concepts (fields/topics) attached by OpenAlex
- Cited by
-
48Total citation count in OpenAlex
- Citations by year (recent)
-
2025: 6, 2024: 1, 2023: 4, 2022: 6, 2021: 10Per-year citation counts (last 5 years)
- References (count)
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61Number of works referenced by this work
- Related works (count)
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10Other works algorithmically related by OpenAlex
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