C/EBPd enables the efficient extravasation of human CCR2+MAIT cells

Abstract Early responses to pathogen challenge depend in part on recruitment of effector-capable T cells from blood. Human mucosal-associated invariant T (MAIT) cells are abundant, mostly CD8+, MR1-restricted, anti-bacterial T cells that could contribute to this response. However, little is known about these cells’ ability to traffic in inflammation. We found that, as compared with non-MAIT CD8+ T cells, human MAIT cells excelled at entering inflamed skin in mice. In flow chamber assays, MAIT cells were efficient at trafficking across activated human umbilical vein endothelial cells (HUVEC) due to high levels of selectin ligands, and chemokine receptors CCR6, and CCR2, which we showed were important for rolling, arrest, and transendothelial migration, respectively. We found that MAIT cells express high levels of the mRNAs for FUT7 and ST3GAL4, which are critical for synthesizing selectin ligands. We also found that expression of FUT7, ST3GAL4, and CCR6 depends on C/EBPd, a bZIP transcription factor that we discovered is expressed preferentially in MAIT cells and that binds to the FUT7, ST3GAL4, and CCR6 promoters. For MAIT cells, knockdown of C/EBPd decreased rolling and arrest on HUVEC and extravasation into inflamed mouse skin. Thus, CCR2+ MAIT cells display trafficking abilities that depend on chemokine receptors with non-redundant roles and the cooperative activities of C/EBPd-regulated genes - and exemplify effector-ready T cells that express a coordinated program enabling rapid entry into sites of inflammation.