Endothelial STING controls T cell transmigration in an IFNI-dependent manner
Marina Anastasiou, Gail A. Newton, Kuljeet Kaur, Francisco J. Carrillo-Salinas, Sasha A. Smolgovsky, Abraham L. Bayer, Vladimir Ilyukha, Shruti Sharma, Alexander Poltorak, Francis W. Luscinskas, Pilar Alcaide
Marina Anastasiou, Gail A. Newton, Kuljeet Kaur, Francisco J. Carrillo-Salinas, Sasha A. Smolgovsky, Abraham L. Bayer, Vladimir Ilyukha, Shruti Sharma, Alexander Poltorak, Francis W. Luscinskas, Pilar Alcaide
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Research Article Inflammation Vascular biology

Endothelial STING controls T cell transmigration in an IFNI-dependent manner

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.

Authors

Marina Anastasiou, Gail A. Newton, Kuljeet Kaur, Francisco J. Carrillo-Salinas, Sasha A. Smolgovsky, Abraham L. Bayer, Vladimir Ilyukha, Shruti Sharma, Alexander Poltorak, Francis W. Luscinskas, Pilar Alcaide

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Figure 2

STING deficiency in EC but not in T cells results in impaired TEM in response to TNF-α.

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STING deficiency in EC but not in T cells results in impaired TEM in res...
(A) Cultured MHEC from WT and STING–/– mice were lysed and analyzed by immunoblot to evaluate STING expression and β-actin, used as a loading control. (B and C) Quantification of adhesion and %TEM of WT and STING–/– Th1 cells perfused across WT and STING–/– MHEC (for WT Th1 groups: n = 3 independent experiments with WT and STING–/– MHEC preparations and Th1 preparations, using duplicate or triplicate coverslips). (D) Representative images of WT and STING–/– Th1 cell adhesion on ICAM1- and VCAM1-coated coverslips following perfusion under flow conditions. Scale bar: 100 μm. (E and F) Quantification of Th1 adhesion on ICAM1 (n = 3 independent experiments, triplicate coverslips) and on VCAM1 (n = 3 independent experiments). (G and H) Representative flow cytometry histograms and quantification of VLA-4 (G) and of LFA-1 (H) from WT and STING–/– Th1 cells (n = 3 independent Th1 cell preparations). Data are shown as mean ± SEM. ***P < 0.001; 1-way ANOVA (B and C) and t test (E and H).