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Stalling Instead of Crawling Allows CD8+ T cells to Cross the Blood-Brain Barrier

Henriette Rudolph1*, Armelle Klopstein2 and Britta Engelhardt2

1Pediatric Infectious Diseases, University Children’s Hospital, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

2Theodor Kocher Institute, University of Bern, 3012 Bern, Germany

*Corresponding Author:
Henriette Rudolph
Pediatric Infectious Diseases, University Children’s Hospital
Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
E-mail: [email protected]

Received date: April 11, 2017; Accepted date: June 07, 2017; Published date: June 14, 2017

Citation: Rudolph H, Klopstein A, Engelhardt B (2017) Stalling Instead of Crawling Allows CD8+ T cells to Cross the Blood-Brain Barrier. J Cell Signal 2:150.

Copyright: © 2017 Rudolph H, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Commentary

In the context of neuroinflammation, circulating T lymphocytes have been shown to extravasate across the blood-brain barrier (BBB) via a well explored multistep process [1-4]. Starting with P-selectin glycoprotein-1 (PSGL-1)-mediated T cell rolling on endothelial P-selectin, T cells will slow down on the inflamed BBB and then interact with chemokines or lipid mediators on the surface of the endothelium engaging G-protein coupled receptors (GPCRs) [1,2,5]. GPCR-mediated inside-out-signaling induces affinity maturation of constitutively expressed integrins on the T cell surface which is prerequisite for integrin-mediated arrest on their endothelial ligands from the Ig-superfamily [1,2]. Important interaction partners for T-cell arrest identified between encephalitogenic CD4+ T cells and the inflamed BBB are endothelial VCAM-1 and α4β1-integrin (VLA4) as well as endothelial ICAM-1 and LFA-1 [2,6,7]. Subsequent crawling of CD4+ T cells over long distances against the direction of flow has been demonstrated in vivo in the context of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis [8]. In vitro studies have shown that interaction of T cell LFA-1 with endothelial ICAM-1 and ICAM-2 is essential for CD4+ T cell crawling [9]. CD8+ T cells have been suggested to be of major importance in the pathogenesis of multiple sclerosis [10]. However, the currently used EAE model is a CD4+ T cell mediated disease model and not suitable to study CD8+ T-cell extravasation across the inflamed BBB in vivo.

In this context, our recent study [11] has aimed to improve our understanding of the cellular and molecular mechanisms mediating CD8+ vs. CD4+ T-cell migration across the BBB in neuroinflammation. Employing in vitro live cell imaging in a microfluidic device the multi-step extravasation of activated CD4+ and CD8+ T cells across primary mouse brain endothelial cells (pMBMECs) as an in vitro model for the BBB was compared side by side. Compared to CD4+ T cells, CD8+ T cells showed a significantly increased shear resistant arrest on pMBMECs stimulated or not with the proinflammatory cytokines INFγ and TNFα.

Interestingly, the arrest of both T cell subsets was not dependent on Gαi-mediated GPCR-mediated integrin affinity maturation. This is in line with previous studies which have shown that Teffector/memory cells express sufficient amounts of high-affinity LFA-1 on their surface which allows for binding to its endothelial ligands in the absence of additional stimuli [2,4,12-14]. Endothelial ICAM-1 and ICAM-2 were of major importance for sufficient T cells arrest of CD8+ T cells, as their absence led to a complete abrogation of enhanced CD8+ T cell arrest compared with CD4+ T cell arrest. This suggests a major involvement of LFA-1 in the process of shear-resistant arrest of CD8+ over CD4+ T cells on pMBMECs. Although CD4 and CD8 T cells were found to express similar cell surface levels of LFA-1 we found CD8 T cells engage higher levels of soluble ICAM-1 suggesting that they display a higher fraction of high affinity LFA-1 on their surface than CD4 T cells (Figure 1).

cell-signaling-lymphocytes-across

Figure 1: Schematic representation of the pathway of diapedesis of activated CD4+ and CD8+ T lymphocytes across pMBMEC in vitro under flow: Side-by-side comparing of the multi-step extravasation of activated CD4+ and CD8+ T cells across the blood-brain barrier (BBB) under flow by in vitro live cell imaging identified subset specific mechanisms of interaction. CD8+ T cells arrested in significantly higher numbers, stalled and crossed the BBB preferentially via the transcellular route.

CD8+ T cell arrest was followed by a unique behavior, where CD8+ T cells would remain localized within their diameter, but visibly and actively probed the endothelium for sites of diapedesis. We classified this behavior as “stalling” in contrast to the behavior of CD4+ T cells which after initial arrest crawled over the endothelial surface prior to their diapedesis as described before [8,9,15]. In correlation to their stalling behavior, transmigration of CD8+ T cells occurred mostly via the transcellular route. In the absence of ICAM-1 and ICAM-2 CD8+ T cells were found to still quite efficiently cross the BBB underscoring that they do not rely as CD4 T cells on ICAM-1 and ICAM-2 mediated crawling for finding a site for diapedesis. Rather the mainly LFA-1/ ICAM-1 and ICAM-2 mediated arrest and stalling of CD8+ T cells on the BBB seemed to lead to optimized interactions with endothelial signaling cascades involved in the formation of ICAM-1 and/or ICAM-2 enriched docking structures that are important for T cell diapedesis [9,15-18].

Taken together our study demonstrated that the cellular and molecular mechanisms involved in the multistep cascade of CD8+ vs. CD4+ T-cell migration across the BBB shows significant differences. Further investigations are thus desirable in order to discover mechanisms unique to different T cell subsets. This will allow the development of more specific treatments targeting the CNS invasion of destructive T cells without affecting CNS immunosurveillance.

Acknowledgements

This work was funded by the Swiss National Science Foundation grant N° 31003A_149420, the Swiss MS Society and ARSEP to BE. HR was funded by fellowship from the DGPI (German Society of Pediatric Infectious Diseases) and the University of Heidelberg (Olympia Morata). The Microscopy Imaging Center of the University of Bern is acknowledged for continuous support.

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