Differential Roles for Endothelial ICAM-1, ICAM-2, and VCAM-1 in Shear-Resistant T Cell Arrest, Polarization, and Directed Crawling on Blood-Brain Barrier Endothelium

Theodor Kocher Institute, University of Bern, Bern, Switzerland.
The Journal of Immunology (Impact Factor: 4.92). 10/2010; 185(8):4846-55. DOI: 10.4049/jimmunol.0903732
Source: PubMed


Endothelial ICAM-1 and ICAM-2 were shown to be essential for T cell diapedesis across the blood-brain barrier (BBB) in vitro under static conditions. Crawling of T cells prior to diapedesis was only recently revealed to occur preferentially against the direction of blood flow on the endothelial surface of inflamed brain microvessels in vivo. Using live cell-imaging techniques, we prove that Th1 memory/effector T cells predominantly crawl against the direction of flow on the surface of BBB endothelium in vitro. Analysis of T cell interaction with wild-type, ICAM-1-deficient, ICAM-2-deficient, or ICAM-1 and ICAM-2 double-deficient primary mouse brain microvascular endothelial cells under physiological flow conditions allowed us to dissect the individual contributions of endothelial ICAM-1, ICAM-2, and VCAM-1 to shear-resistant T cell arrest, polarization, and crawling. Although T cell arrest was mediated by endothelial ICAM-1 and VCAM-1, T cell polarization and crawling were mediated by endothelial ICAM-1 and ICAM-2 but not by endothelial VCAM-1. Therefore, our data delineate a sequential involvement of endothelial ICAM-1 and VCAM-1 in mediating shear-resistant T cell arrest, followed by endothelial ICAM-1 and ICAM-2 in mediating T cell crawling to sites permissive for diapedesis across BBB endothelium.

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    • "Consistent with this fact, it is shown that combinational treatment with anti-MAdCAM-1, VCAM-1 and ICAM-1 monoclonal antibodies led to more rapid remission in the experimental autoimmune encephalitis (EAE) model of MS than that obtained with individual antibodies alone [39]. Similarly, Steiner et al., found that ICAM-1 and VCAM-1 have redundant roles in mediating shear resistant arrest of encephalitogenic T cells to the BBB endothelial cells and only in the functional absence of both was the complete abrogation of T cell arrest on the BBB observed [40]. "
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    • "Both DC-SIGNR and DC-SIGN lectins are expressed on sinusoidal endothelial cells and recognize the Lewis sugars (Lai et al., 2006). ICAM-2 is normally glycosylated with Lewis(Y), and is involved in T-cell recruitment across activated brain endothelial cells (Steiner et al., 2010). Lewis(Y) binds to DC-SIGN, and it has been suggested that the interaction between ICAM-2 and DC-SIGN is an early event in dendritic cell recruitment to the CNS (Arjmandi et al., 2009). "

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