Cytotoxic T Cells Mediate Pathology and Metastasis in Cutaneous Leishmaniasis

PLoS Pathogens

Camila I. de Oliveira¹  Daniel P. Beiting²  David S. Roos²  Michael R. Betts³  Fernanda O. Novais⁴  Phillip Scott⁴  Michael H. Goldschmidt⁴  Gordon Ruthel⁴  Lucas P. Carvalho⁵  Mary E. Wilson⁶  Joel W. Graff⁶ 

[1] Centro de Pesquisas Gonçalo Moniz, Fundaçao Oswaldo Cruz, Salvador, Brazil;Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America;Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America;Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America;Instituto Nacional de Ciência e Tecnologia de Doenças Tropicais-INCT-DT(CNPq/MCT), Serviço de Imunologia, Hospital Universitario Prof. Edgard Santos, Universidade Federal da Bahia Salvador, Bahia, Brazil;Iowa City VA Medical Center, Iowa City, Iowa, United States of America

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

DOI  :  10.1371/journal.ppat.1003504

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY