Journal article
Cytotoxic T Cells Mediate Pathology and Metastasis in Cutaneous Leishmaniasis
PLoS pathogens, Vol.9(7), pp.e1003504-e1003504
07/18/2013
DOI: 10.1371/journal.ppat.1003504
PMCID: PMC3715507
PMID: 23874205
Abstract
Disease progression in response to infection can be strongly influenced by both pathogen burden and infection-induced immunopathology. While current therapeutics focus on augmenting protective immune responses, identifying therapeutics that reduce infection-induced immunopathology are clearly warranted. Despite the apparent protective role for murine CD8+ T cells following infection with the intracellular parasite
Leishmania
, CD8+ T cells have been paradoxically linked to immunopathological responses in human cutaneous leishmaniasis. Transcriptome analysis of lesions from
Leishmania braziliensis
patients revealed that genes associated with the cytolytic pathway are highly expressed and CD8+ T cells from lesions exhibited a cytolytic phenotype. To determine if CD8+ T cells play a causal role in disease, we turned to a murine model. These studies revealed that disease progression and metastasis in
L. braziliensis
infected mice was independent of parasite burden and was instead directly associated with the presence of CD8+ T cells. In mice with severe pathology, we visualized CD8+ T cell degranulation and lysis of
L. braziliensis
infected cells. Finally, in contrast to wild-type CD8+ T cells, perforin-deficient cells failed to induce disease. Thus, we show for the first time that cytolytic CD8+ T cells mediate immunopathology and drive the development of metastatic lesions in cutaneous leishmaniasis.
Leishmaniasis is a parasitic disease where the host immune response plays an essential role in pathogenesis. However, the mechanisms promoting immunopathology in patients are still unclear. We performed gene expression profiling of skin lesions from cutaneous leishmaniasis patients and normal skin and the results demonstrated that the most expressed genes in leishmanial lesions were associated with the cytolytic pathway. Using both human samples and mouse models we showed that CD8+ T cells are cytolytic within leishmanial lesions and kill
Leishmania
infected target cells. We found that the CD8+ T cell cytolytic response was not protective, but rather promoted increased immunopathology, associated with enhanced recruitment of neutrophils to the site of infection. CD8+ T cells also promoted the development of metastatic lesions at distant skin sites. Together, our results clearly demonstrate that activation of CD8+ T cell cytolytic responses is detrimental to the host and that targeting this pathway could be a new approach to treat patients with leishmaniasis.
Details
- Title: Subtitle
- Cytotoxic T Cells Mediate Pathology and Metastasis in Cutaneous Leishmaniasis
- Creators
- Fernanda O NovaisLucas P CarvalhoJoel W GraffDaniel P BeitingGordon RuthelDavid S RoosMichael R BettsMichael H GoldschmidtMary E WilsonCamila I de OliveiraPhillip Scott
- Resource Type
- Journal article
- Publication Details
- PLoS pathogens, Vol.9(7), pp.e1003504-e1003504
- DOI
- 10.1371/journal.ppat.1003504
- PMID
- 23874205
- PMCID
- PMC3715507
- NLM abbreviation
- PLoS Pathog
- ISSN
- 1553-7366
- eISSN
- 1553-7374
- Publisher
- Public Library of Science; San Francisco, USA
- Alternative title
- Pathogenic CD8+ T Cells in Cutaneous Leishmanaisis
- Language
- English
- Date published
- 07/18/2013
- Academic Unit
- Microbiology and Immunology; International Programs; Epidemiology; Internal Medicine
- Record Identifier
- 9984001145002771
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