title: Cytotoxic T cells mediate pathology and metastasis in cutaneous leishmaniasis.
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.
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Fernanda O
authors.initials: FO
authors.lastname: Novais
authors.forename: Lucas P
authors.initials: LP
authors.lastname: Carvalho
authors.forename: Joel W
authors.initials: JW
authors.lastname: Graff
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Beiting
authors.forename: Gordon
authors.initials: G
authors.lastname: Ruthel
authors.forename: David S
authors.initials: DS
authors.lastname: Roos
authors.forename: Michael R
authors.initials: MR
authors.lastname: Betts
authors.forename: Michael H
authors.initials: MH
authors.lastname: Goldschmidt
authors.forename: Mary E
authors.initials: ME
authors.lastname: Wilson
authors.forename: Camila I
authors.initials: CI
authors.lastname: de Oliveira
authors.forename: Phillip
authors.initials: P
authors.lastname: Scott
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D001938:Brazil; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D018450:Disease Progression; D020869:Gene Expression Profiling; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007892:Leishmania braziliensis / Q000276:immunology* / Q000302:isolation & purification; D016773:Leishmaniasis, Cutaneous / Q000276:immunology* / Q000469:parasitology / Q000473:pathology / Q000503:physiopathology; D016774:Leishmaniasis, Diffuse Cutaneous / Q000209:etiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012867:Skin / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D013047:Specific Pathogen-Free Organisms; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000469:parasitology / Q000473:pathology
chemical_list: D001426:Bacterial Proteins; D018398:Homeodomain Proteins; C064658:RAG-1 protein