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 1

Impaired leukocyte recruitment in response to TNF-α–induced peritonitis in STING–/– mice compared with WT mice.

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Impaired leukocyte recruitment in response to TNF-α–induced peritonitis ...
(A–H) WT and STING–/– mice received PBS, TNF-α 4 hours (h), or TNF-α 24 h (A–D) or thioglycollate 3 days (E–H) via i.p. injection, and the peritoneal lavage was analyzed by FACS. (A) Representative flow cytometric panels of CD45+CD4+ cells recruited to the peritoneal cavity at 24 h and of CD45+Gr1+ at 4 h. (B–D) Quantification of total CD45+ (B), CD45+CD4+ (C), and CD45+Gr1+ (D) recruited to the peritoneal cavity. n = 3 (control); n = 12 (TNF-α 24 h); n = 3-4 (TNF-α 4 h). (E) Representative flow cytometric panels of CD45+CD11b+ cells recruited to the peritoneal cavity in response to thioglycolate of 3 independent experiments. (F–H) Quantification of CD45+ (F), CD45+CD11b+ (G), and CD45+CD4+ (H) recruited cells to the peritoneal cavity. n = 3 (control); n = 8 (thioglycollate). Data are shown as mean ± SEM values. *P < 0.05 and **P < 0.01; 2-way ANOVA (B–D) and 1-way ANOVA (F–H).