Many mediators and regulators of extravasation by bona fide human memory-phenotype T cells remain undefined. Mucosal-associated invariant T (MAIT) cells are innate-like, anti-bacterial cells that we found excelled at crossing inflamed endothelium. They displayed abundant selectin ligands, with high expression of FUT7 and ST3GAL4, and expressed CCR6, CCR5, and CCR2, which played non-redundant roles in trafficking on activated endothelial cells. MAIT cells selectively expressed CCAAT/enhancer-binding protein delta (C/EBPδ). Knockdown of C/EBPδ diminished expression of FUT7, ST3GAL4 and CCR6, decreasing MAIT cell rolling and arrest, and consequently the cells' ability to cross an endothelial monolayer in vitro and extravasate in mice. Nonetheless, knockdown of C/EBPδ did not affect CCR2, which was important for the step of transendothelial migration. Thus, MAIT cells demonstrate a program for extravasastion that includes, in part, C/EBPδ and C/EBPδ-regulated genes, and that could be used to enhance, or targeted to inhibit T cell recruitment into inflamed tissue.
- Joshua M Farber
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NIAID approved submission per standard Institute procedures.
Animal experimentation: Mice were housed under specific pathogen free conditions at the National Institutes of Health in an American Association for the Accreditation of Laboratory Animal Care-approved facility. Animals were studied under protocol LMI-13 as approved by the Animal Care and Use Committee, NIAID, NIH.
Human subjects: Human blood cells were obtained by the Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, under protocol 99-CC-0168 approved by the Institutional Review Board. Informed consent was obtained after explanation of the risks.
- Wayne M Yokoyama, Howard Hughes Medical Institute, Washington University School of Medicine, United States
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