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 5

T cell TEM is dependent of EC JAK/STAT and IFNI.

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T cell TEM is dependent of EC JAK/STAT and IFNI. (A) Schematic of IFN-α ...
(A) Schematic of IFN-α and IFN-β molecules binding to the heterodimeric IFNAR and signal through JAK1 to recruit STAT1. (B) Representative heatmap corresponding to log2 values from RNA-seq of WT and STING–/– control and 4-h TNF-α–stimulated MHEC (n = 3 mice/group were pulled for RNA-seq). (C) qPCR validation of STAT1 and the indicated ISG in WT and STING–/– control and 4-h TNF-α–stimulated MHEC (n = 3 independent MHEC preparations, n = 2 replicates per condition). (D) Quantification of WT Th1 T cell accumulation. (E) WT Th1 T cell %TEM across 4-h TNF-α–stimulated MHEC treated with JAK1 inhibitor BAR. n = 3 independent experiments (duplicate coverslips for control). (F) Quantification of human CD3+ T cell %TEM across 4-h TNF-α–stimulated HUVEC with IFNAR blockade. n = 4 independent experiments, triplicate coverslips. Data are mean ± SEM. *P < 0.05; t test.