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...
Main Authors: | , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2013-01-01
|
Series: | PLoS Pathogens |
Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23874205/pdf/?tool=EBI |
id |
doaj-4f7dec74ed9c4d0dbd09cd51d83320cd |
---|---|
record_format |
Article |
spelling |
doaj-4f7dec74ed9c4d0dbd09cd51d83320cd2021-04-21T17:09:48ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742013-01-0197e100350410.1371/journal.ppat.1003504Cytotoxic T cells mediate pathology and metastasis in cutaneous leishmaniasis.Fernanda O NovaisLucas P CarvalhoJoel W GraffDaniel P BeitingGordon RuthelDavid S RoosMichael R BettsMichael H GoldschmidtMary E WilsonCamila I de OliveiraPhillip ScottDisease 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.https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23874205/pdf/?tool=EBI |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Fernanda O Novais Lucas P Carvalho Joel W Graff Daniel P Beiting Gordon Ruthel David S Roos Michael R Betts Michael H Goldschmidt Mary E Wilson Camila I de Oliveira Phillip Scott |
spellingShingle |
Fernanda O Novais Lucas P Carvalho Joel W Graff Daniel P Beiting Gordon Ruthel David S Roos Michael R Betts Michael H Goldschmidt Mary E Wilson Camila I de Oliveira Phillip Scott Cytotoxic T cells mediate pathology and metastasis in cutaneous leishmaniasis. PLoS Pathogens |
author_facet |
Fernanda O Novais Lucas P Carvalho Joel W Graff Daniel P Beiting Gordon Ruthel David S Roos Michael R Betts Michael H Goldschmidt Mary E Wilson Camila I de Oliveira Phillip Scott |
author_sort |
Fernanda O Novais |
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. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Pathogens |
issn |
1553-7366 1553-7374 |
publishDate |
2013-01-01 |
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. |
url |
https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23874205/pdf/?tool=EBI |
work_keys_str_mv |
AT fernandaonovais cytotoxictcellsmediatepathologyandmetastasisincutaneousleishmaniasis AT lucaspcarvalho cytotoxictcellsmediatepathologyandmetastasisincutaneousleishmaniasis AT joelwgraff cytotoxictcellsmediatepathologyandmetastasisincutaneousleishmaniasis AT danielpbeiting cytotoxictcellsmediatepathologyandmetastasisincutaneousleishmaniasis AT gordonruthel cytotoxictcellsmediatepathologyandmetastasisincutaneousleishmaniasis AT davidsroos cytotoxictcellsmediatepathologyandmetastasisincutaneousleishmaniasis AT michaelrbetts cytotoxictcellsmediatepathologyandmetastasisincutaneousleishmaniasis AT michaelhgoldschmidt cytotoxictcellsmediatepathologyandmetastasisincutaneousleishmaniasis AT maryewilson cytotoxictcellsmediatepathologyandmetastasisincutaneousleishmaniasis AT camilaideoliveira cytotoxictcellsmediatepathologyandmetastasisincutaneousleishmaniasis AT phillipscott cytotoxictcellsmediatepathologyandmetastasisincutaneousleishmaniasis |
_version_ |
1714666483786711040 |