201. Endothelial STING controls T cell transmigration in an IFNI-dependent manner.
- Author
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Anastasiou M, Newton GA, Kaur K, Carrillo-Salinas FJ, Smolgovsky SA, Bayer AL, Ilyukha V, Sharma S, Poltorak A, Luscinskas FW, and Alcaide P
- Subjects
- Animals, Immunity, Innate, Intercellular Adhesion Molecule-1 immunology, Mice, Signal Transduction immunology, Tumor Necrosis Factor-alpha metabolism, Vascular Cell Adhesion Molecule-1 immunology, Interferon Type I immunology, Interferon Type I metabolism, Membrane Proteins immunology, Receptor, Interferon alpha-beta immunology, Receptor, Interferon alpha-beta metabolism, T-Lymphocytes immunology, T-Lymphocytes metabolism, Transendothelial and Transepithelial Migration immunology
- Abstract
The stimulator of IFN genes (STING) protein senses cyclic dinucleotides released in response to double-stranded DNA and functions as an adaptor molecule for type I IFN (IFNI) signaling by activating IFNI-stimulated genes (ISG). We found impaired T cell infiltration into the peritoneum in response to TNF-α in global and EC-specific STING-/- mice and discovered that T cell transendothelial migration (TEM) across mouse and human endothelial cells (EC) deficient in STING was strikingly reduced compared with control EC, whereas T cell adhesion was not impaired. STING-/- T cells showed no defect in TEM or adhesion to EC, or immobilized endothelial cell-expressed molecules ICAM1 and VCAM1, compared with WT T cells. Mechanistically, CXCL10, an ISG and a chemoattractant for T cells, was dramatically reduced in TNF-α-stimulated STING-/- EC, and genetic loss or pharmacologic antagonisms of IFNI receptor (IFNAR) pathway reduced T cell TEM. Our data demonstrate a central role for EC-STING during T cell TEM that is dependent on the ISG CXCL10 and on IFNI/IFNAR signaling.
- Published
- 2021
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