Delivery of Cytotoxic Vesicles by Human CD8+ T Cell Extracellular Traps Mediates Cell Death and Pathology

Abstract

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, exert microbicidal activity, and is often associated with innate immune cells. Here we demonstrate that human CD8+ T cells release ETs (herein LETs – lymphocyte extracellular traps), which display unique morphology and functional characteristics. CD8+ T cell-derived LETs form strands that connect distant cells and colocalize with CD107a, a cytotoxicity marker. The release of LETs by CD8+ T cells induces death of neighboring cells without intimate cell-cell contact. Importantly, we show that the progression and severity of debilitating and mutilating forms of human leishmaniasis are associated with CD8+ T cell-derived LETs carrying CD107a+ vesicles. We propose that CD8+ T cell-derived LETs deliver cytotoxicity signals to distant target cells causing their death, providing insights into mechanisms of CD8-mediated pathology.