Cytotoxic T Cells Mediate Pathology and Metastasis in Cutaneous Leishmaniasis
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 warran...
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Public Library of Science
2013
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3715507/ |
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pubmed-37155072013-07-19 Cytotoxic T Cells Mediate Pathology and Metastasis in Cutaneous Leishmaniasis Novais, Fernanda O. Carvalho, Lucas P. Graff, Joel W. Beiting, Daniel P. Ruthel, Gordon Roos, David S. Betts, Michael R. Goldschmidt, Michael H. Wilson, Mary E. de Oliveira, Camila I. Scott, Phillip Research Article 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. Public Library of Science 2013-07-18 /pmc/articles/PMC3715507/ /pubmed/23874205 http://dx.doi.org/10.1371/journal.ppat.1003504 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. |
| repository_type |
Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Novais, Fernanda O. Carvalho, Lucas P. Graff, Joel W. Beiting, Daniel P. Ruthel, Gordon Roos, David S. Betts, Michael R. Goldschmidt, Michael H. Wilson, Mary E. de Oliveira, Camila I. Scott, Phillip |
| spellingShingle |
Novais, Fernanda O. Carvalho, Lucas P. Graff, Joel W. Beiting, Daniel P. Ruthel, Gordon Roos, David S. Betts, Michael R. Goldschmidt, Michael H. Wilson, Mary E. de Oliveira, Camila I. Scott, Phillip Cytotoxic T Cells Mediate Pathology and Metastasis in Cutaneous Leishmaniasis |
| author_facet |
Novais, Fernanda O. Carvalho, Lucas P. Graff, Joel W. Beiting, Daniel P. Ruthel, Gordon Roos, David S. Betts, Michael R. Goldschmidt, Michael H. Wilson, Mary E. de Oliveira, Camila I. Scott, Phillip |
| author_sort |
Novais, Fernanda O. |
| title |
Cytotoxic T Cells Mediate Pathology and Metastasis in Cutaneous Leishmaniasis |
| title_short |
Cytotoxic T Cells Mediate Pathology and Metastasis in Cutaneous Leishmaniasis |
| title_full |
Cytotoxic T Cells Mediate Pathology and Metastasis in Cutaneous Leishmaniasis |
| title_fullStr |
Cytotoxic T Cells Mediate Pathology and Metastasis in Cutaneous Leishmaniasis |
| title_full_unstemmed |
Cytotoxic T Cells Mediate Pathology and Metastasis in Cutaneous Leishmaniasis |
| title_sort |
cytotoxic t cells mediate pathology and metastasis in cutaneous leishmaniasis |
| description |
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. |
| publisher |
Public Library of Science |
| publishDate |
2013 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3715507/ |
| _version_ |
1611995995546058752 |