Primate Monocytes - CD14, CD16 - Ziegler-Heitbrock

Regulation of Synovial gammadelta T Cell Ligand Expression by Mitochondrial Reactive Oxygen Species and Gasdermin-D.

Abstract

gammadelta T cells reside at mucosal and epithelial barriers, and they often accumulate at sites of inflammation, both infectious and autoimmune, as well as in certain tumors. However, progress in understanding their function is considerably hampered by a lack of full understanding of the ligands recognized by TCR-gammadelta and how expression of these ligands is regulated. We recently developed a soluble human TCR-gammadelta (Vgamma9Vdelta1) tetramer from a synovial gammadelta T cell clone of a Lyme arthritis patient and observed that it stains monocytes activated by Borrelia burgdorferi. Those findings are extended in the current study to further examine the physiological regulation of ligand expression on monocytes. The TCR-gammadelta ligand is induced by a variety of TLR agonists and requires NF-kappaB activation. Of particular interest is that ligand expression also requires caspase activation of the inflammasome and is dependent on active metabolism, mitochondrial reactive oxygen species, and activation of gasdermin-D. Consistent with these observations, the TCR-gammadelta ligand is expressed by a subset of metabolically active CD14+CD16+ monocytes and colocalizes intracellularly with mitochondria. The findings suggest a model in which synovial gammadelta T cell ligand is a self-antigen whose surface expression is increased by inflammatory conditions and mitochondrial stress.