title: CD8+ T cell cytotoxicity mediates pathology in the skin by inflammasome activation and IL-1β production.
abstract: Deregulated CD8+ T cell cytotoxicity plays a central role in enhancing disease severity in several conditions. However, we have little understanding of the mechanisms by which immunopathology develops as a consequence of cytotoxicity. Using murine models of inflammation induced by the protozoan parasite leishmania, and data obtained from patients with cutaneous leishmaniasis, we uncovered a previously unrecognized role for NLRP3 inflammasome activation and IL-1β release as a detrimental consequence of CD8+ T cell-mediated cytotoxicity, ultimately resulting in chronic inflammation. Critically, pharmacological blockade of NLRP3 or IL-1β significantly ameliorated the CD8+ T cell-driven immunopathology in leishmania-infected mice. Confirming the relevance of these findings to human leishmaniasis, blockade of the NLRP3 inflammasome in skin biopsies from leishmania-infected patients prevented IL-1β release. Thus, these studies link CD8+ T cell cytotoxicity with inflammasome activation and reveal novel avenues of treatment for cutaneous leishmaniasis, as well as other of diseases where CD8+ T cell-mediated cytotoxicity induces pathology.
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.affiliation: Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Bahia, Brazil.
authors.forename: Augusto M
authors.initials: AM
authors.lastname: Carvalho
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Megan L
authors.initials: ML
authors.lastname: Clark
authors.affiliation: Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Bahia, Brazil.|Serviço de Imunologia, Complexo Hospitalar Prof. Edgard Santos, Universidade Federal da Bahia, Salvador, Bahia, Brazil.|Instituto Nacional de Ciências e Tecnologia-Doenças Tropicais, Salvador, Bahia, Brazil.
authors.forename: Lucas P
authors.initials: LP
authors.lastname: Carvalho
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Beiting
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Igor E
authors.initials: IE
authors.lastname: Brodsky
authors.affiliation: Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Bahia, Brazil.|Serviço de Imunologia, Complexo Hospitalar Prof. Edgard Santos, Universidade Federal da Bahia, Salvador, Bahia, Brazil.|Instituto Nacional de Ciências e Tecnologia-Doenças Tropicais, Salvador, Bahia, Brazil.
authors.forename: Edgar M
authors.initials: EM
authors.lastname: Carvalho
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Phillip
authors.identifier: 0000-0001-8732-0653
authors.initials: P
authors.lastname: Scott
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D058847:Inflammasomes / Q000276:immunology*; D053583:Interleukin-1beta / Q000096:biosynthesis* / Q000276:immunology; D007892:Leishmania braziliensis; D016773:Leishmaniasis, Cutaneous / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000276:immunology; D060888:Real-Time Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein