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

Abstract

γδ 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-γδ and how expression of these ligands is regulated. We recently developed a soluble human TCR-γδ (Vγ9Vδ1) tetramer from a synovial γδ 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-γδ ligand is induced by a variety of TLR agonists and requires NF-κB 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-γδ 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 γδ T cell ligand is a self-antigen whose surface expression is increased by inflammatory conditions and mitochondrial stress.

Gasdermins assemble; recent developments in bacteriology and pharmacology

“…Particularly interesting is that this mechanism is evolutionary conserved as the authors show both LRRK2 G2019S expressing flies infected with Pseudomonas entomophila and LRRK2 G2019S mice infected with Mycobacterium tuberculosis exhibit hyperinflammation, higher bacterial burden and enhanced immunopathology ( 32 ). This mitochondrial ROS-GSDMD axis is also seen to be important in surface expression of the synovial T cell receptor-γδ ligand on CD14 + CD16 + monocytes, in conjunction with toll-like receptor (TLR) stimulation, mitochondrial metabolism and inflammasome activation in a redox sensitive manner ( 67 ). This is important in regulating the response of γδ T cells in infection and autoimmunity, where overactive GSDMD may contribute to overexpression of surface γδ ligand, driving aberrant adaptive immune response, and targeting GSDMD at the mitochondrial ROS-GSDMD axis in inflammatory monocytes may provide a useful approach.…”