Human CD8+ T Cells Release Extracellular Traps Co-Localized With Cytotoxic Vesicles That Are Associated With Lesion Progression and Severity in Human Leishmaniasis

Cell death plays a fundamental role in mounting protective and pathogenic immunity. Etosis is a cell death mechanism defined by the release of extracellular traps (ETs), which can foster inflammation and exert microbicidal activity. While etosis is often associated with innate cells, recent studies...

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Published in:	Frontiers in immunology Vol. 11; p. 594581
Main Authors:	Koh, Carolina Cattoni, Wardini, Amanda B, Vieira, Millene, Passos, Livia S A, Martinelli, Patrícia Massara, Neves, Eula Graciele A, Antonelli, Lis Riberido do Vale, Barbosa, Daniela Faria, Velikkakam, Teresiama, Gutseit, Eduardo, Menezes, Gustavo B, Giunchetti, Rodolfo Cordeiro, Machado, Paulo Roberto Lima, Carvalho, Edgar M, Gollob, Kenneth J, Dutra, Walderez Ornelas
Format:	Journal Article
Language:	English
Published:	Switzerland Frontiers Media S.A 08-10-2020
Subjects:	CD8+ T cells cytotoxicity etosis extracellular traps Immunology leishmaniasis pathology extracellular traps CD8+ T cells pathology leishmaniasis etosis cytotoxicity
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Summary:	Cell death plays a fundamental role in mounting protective and pathogenic immunity. Etosis is a cell death mechanism defined by the release of extracellular traps (ETs), which can foster inflammation and exert microbicidal activity. While etosis is often associated with innate cells, recent studies showed that B cells and CD4+ T cells can release ETs. Here we investigate whether CD8+ T cells can also release ETs, which might be related to cytotoxicity and tissue pathology. To these ends, we first employed an in vitro system stimulating human CD8+ T cells isolated from healthy volunteers with anti-CD3/anti-CD28. Using time-frame video, confocal and electron microscopy, we demonstrate that human CD8+ T cells release ETs upon stimulation (herein LETs - lymphocyte extracellular traps), which display unique morphology and functional characteristics. CD8+ T cell-derived LETs form long strands that co-localize with CD107a, a marker of vesicles containing cytotoxic granules. In addition, these structures connect the LET-releasing cell to other neighboring cells, often resulting in cell death. After demonstrating the release of LETs by human CD8+ T cells in vitro, we went on to study the occurrence of CD8-derived LETs in a human disease setting. Thus, we evaluated the occurrence of CD8-derived LETs in lesions from patients with human tegumentary leishmaniasis, where CD8+ T cells play a key role in mediating pathology. In addition, we evaluated the association of these structures with the intensity of the inflammatory infiltrate in early and late cutaneous, as well as in mucosal leishmaniasis lesions. We demonstrated that progression and severity of debilitating and mutilating forms of human tegumentary leishmaniasis are associated with the frequency of CD8+ T cells in etosis, as well as the occurrence of CD8-derived LETs carrying CD107a+ vesicles in the lesions. We propose that CD8+ T cell derived LETs may serve as a tool for delivering cytotoxic vesicles to distant target cells, providing insights into mechanisms of CD8+ T cell mediated pathology.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 This article was submitted to Microbial Immunology, a section of the journal Frontiers in Immunology Edited by: Roberta Olmo Pinheiro, Oswaldo Cruz Foundation, Brazil Reviewed by: David Sacks, National Institutes of Health (NIH), United States; Claudia Ida Brodskyn, Gonçalo Moniz Institute (IGM), Brazil
ISSN:	1664-3224 1664-3224
DOI:	10.3389/fimmu.2020.594581