CD8+ T cell cytotoxicity mediates pathology in the skin by inflammasome activation and IL-1β production

PLoS Pathogens

Lucas P. Carvalho¹  Augusto M. Carvalho¹  Edgar M. Carvalho²  Fernanda O. Novais²  Phillip Scott²  Megan L. Clark²  Igor E. Brodsky³  Daniel P. Beiting⁴ 

[1] Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Bahia, Brazil;Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America;Instituto Nacional de Ciências e Tecnologia-Doenças Tropicais, Salvador, Bahia, Brazil;Serviço de Imunologia, Complexo Hospitalar Prof. Edgard Santos, Universidade Federal da Bahia, Salvador, Bahia, Brazil

关键词: Cytotoxic T cells;    T cells;    Parasitic diseases;    Mouse models;    Lesions;    Inflammasomes;    Ear infections;    Leishmaniasis;   

DOI  :  10.1371/journal.ppat.1006196

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY