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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Auteurs principaux:	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
Format:	article
Langue:	EN
Publié:	Public Library of Science (PLoS) 2013
Sujets:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Accès en ligne:	https://doaj.org/article/4f7dec74ed9c4d0dbd09cd51d83320cd
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spelling	oai:doaj.org-article:4f7dec74ed9c4d0dbd09cd51d83320cd2021-11-18T06:05:21ZCytotoxic T cells mediate pathology and metastasis in cutaneous leishmaniasis.1553-73661553-737410.1371/journal.ppat.1003504https://doaj.org/article/4f7dec74ed9c4d0dbd09cd51d83320cd2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23874205/pdf/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Disease 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.Fernanda O NovaisLucas P CarvalhoJoel W GraffDaniel P BeitingGordon RuthelDavid S RoosMichael R BettsMichael H GoldschmidtMary E WilsonCamila I de OliveiraPhillip ScottPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 9, Iss 7, p e1003504 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 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.
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.
format	article
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
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)
publishDate	2013
url	https://doaj.org/article/4f7dec74ed9c4d0dbd09cd51d83320cd
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Cytotoxic T cells mediate pathology and metastasis in cutaneous leishmaniasis.

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