Editorial: PSGL‐1—the hidden player in T cell trafficking into the brain in multiple sclerosis?

In MS, a large number of inflammatory cells gain access to the CNS parenchyma, causing inflammation, BBB breakdown, and demyelination, which all pave the way to the development of clinical manifestations of this disabling disease. Studies performed in EAE, a CD4 T cell-mediated rodent model for MS, have helped to elucidate some of the molecular mechanisms involved in immune cell entry into the CNS. In particular, the realization that 4-integrins play a predominant role in T cell trafficking into the CNS in EAE has led to the development of a humanized anti4-integrin antibody as a novel treatment of relapsing-remitting MS [1]. By visualizing the CNS microvasculature using intravital microscopy, it was shown that this antibody specifically inhibits the firm adhesion but not the rolling or capture of human T cells to the inflamed BBB in vivo [2]. Thus, the roles of other adhesion and signaling molecules in the multistep interaction of autoagressive immune cells with the BBB endothelium remain to be investigated, and novel molecules contributing to immune cell entry into the CNS during MS may still be identified. In this issue, Bahbouhi and colleagues [3] propose that an expanded pool of PSGL-1 CD4 memory T cells contributes to brain pathology in MS patients. This statement is based on their investigation of a group of 27 patients with relapsing-remitting MS, exhibiting an increased percentage of circulating CD4 T cells expressing high cell-surface levels of PSGL-1 when compared with healthy individuals. PSGL-1 is a homodimeric sialomucin, which binds to L-, E-, and P-selectin. To serve as a selectin ligand, the protein backbone of PSGL-1 must be decorated with specific carbohydrate side-chains. Although the present study does not address directly whether elevated PSGL-1 protein levels on circulating CD4 T cells of MS patients correlate to enhanced selectin binding by PSGL-1, the authors demonstrate that PSGL-1 CD4 T cells, but not PSGL-1 CD8 T cells, from MS patients showed an enhanced ability to migrate across human brain endothelial cells (Fig. 1). The transmigrated T cell population was enriched for PSGL-1 CD4 CD45RO memory T cells, suggesting functional involvement of PSGL-1 in T cell interaction with brain endothelium in vitro. In fact, besides confirming the known involvement of LFA-1 and 4-integrins in T cell interaction with the BBB, in this study, the authors demonstrate that under static conditions, human peripheral blood T cells adhere to human brain endothelial cells in vitro in a PSGL-1dependent manner. Blocking PSGL-1 was found to reduce T cell adhesion significantly to these brain endothelial cells and their subsequent migration across the brain endothelial monolayer in vitro. Taken together, this study therefore provides direct in vitro evidence for a functional involvement of PSGL-1 in the interaction of peripheral blood T cells with brain endothelium. Considering the expanded pool of PSGL-1CD4 T cells detected in the peripheral blood of the MS patients in the present study, it is temping to speculate that PSGL-1 can be involved in T cell migration across the BBB in MS. All T cells express PSGL-1 protein at the cell surface, but as explained above, the molecule is not functional unless decorated by specific carbohydrate sidechains. Selectin-binding activity of PSGL-1 requires tyrosine-sulfation, fucosylation, and the attachment of O-glycan-linked carbohydrate side-chains to the protein backbone [4]. In contrast to neutrophils and monocytes, T cells do not constitutively express all modifying enzymes required for expression of functional PSGL-1. Specifically, expression of fucosyltransferase VII and C2GlcNAcT-I are up-regulated independently during T cell activation and maturation via the TCR and cytokines including IL-12 (summarized in ref. [5]). PSGL-1-dependent migration of T cells to sites of inflammation is therefore regulated by the inducible expression of functional PSGL-1 and the ex-