Differential adhesion molecule requirements for immune surveillance and inflammatory recruitment

Abstract

Activated CD4 Th1 lymphocytes can enter the brain in the absence of an inflammatory focus. However, the molecular mediators that regulate this early migration of lymphocytes into the brain have remained unclear. We hypothesized that the entry of these 'pioneer' lymphocytes into the brain is regulated by a set of molecular events that are distinct from those used once inflammation has been established. Using cells fluorescently labelled with the lipophilic dye DiI, myelin basic protein (MBP)-specific CD4 lymphocytes that expressed low or high levels of very late antigen-4 (VLA-4) and non-antigen-specific activated splenocytes homed to mouse brain in similar quantities 2 h after adoptive transfer. However, antigen specificity and VLA-4 expression were required for more robust recruitment by 24 h. Immunocytochemistry revealed endothelial and microenvironmental upregulation of vascular cell adhesion molecule (VCAM), intercellular cell adhesion molecule 1 (ICAM-1), MHC class II and interferon-gamma 48 h after transfer of MBP-specific cells. In contrast, expression of meningeal and choroid plexus-associated P selectin was upregulated 2 h after adoptive transfer, but not at 48 h. Monoclonal antibody to P selectin, but not to VLA-4, inhibited early migration of high VLA-4-expressing MBP-specific lymphocytes. These results suggest that early migration occurs independent of the lymphocyte integrin VLA-4 and endothelial VCAM, but does require increased surface expression of endothelial P selectin.

Human cerebrospinal fluid central memory CD4+T cells: Evidence for trafficking through choroid plexus and meninges via P-selectin

“…P-selectin binding through ligands presented on PSGL-1 is required for circulating murine T cells to enter the intrathecal compartment, in a migration pattern that is proposed to support immune surveillance of the CNS (17). We found that all CD4 ϩ ͞CD45RO ϩ T cells in CSF from patients with NIND, as in PB, expressed PSGL-1 (Fig.…”

“…Pioneer lymphocytes, proposed to perform immune surveillance, were detected in murine choroid plexus and leptomeninges (5,17). To assess whether human T cells might traffic similarly, we analyzed sections of choroid plexus from seven individuals.…”

“…In the present study, T cells were detected in the choroidal stroma, providing indirect proof that lymphocytes traffic through this location in humans. Cell recruitment through the SAS and choroid plexus has been proposed to be of particular importance during immune surveillance of the healthy CNS because blockade of P-selectin inhibited early migration of labeled T cells into the noninflamed brain at a time point when anti-very late antigen 4 antibodies had no suppressive effect (17). Our studies demonstrated that the majority of CD4 ϩ ͞CD45RO ϩ T cells in both blood and CSF expressed PSGL-1, one of the proteins capable of presenting the carbohydrate ligands for P-and E-selectin.…”

E- and P-Selectin Are Not Required for the Development of Experimental Autoimmune Encephalomyelitis in C57BL/6 and SJL Mice

“…Interestingly, the differences between meningeal and parenchymal CNS blood vessel endothelial cells extend to differences in their expression patterns for P-and E-selectin. In the healthy CNS, meningeal blood vessel endothelial cells can be distinguished from those in the CNS parenchyma by their constitutive expression of P-selectin, which is absent from endothelial cells of parenchymal blood vessels (17,28). Furthermore, injection of proinflammatory cytokines into mice induced expression of E-selectin in meningeal but not in parenchymal CNS blood vessel endothelial cells (25).…”

In Vivo Blockade of Macrophage Migration Inhibitory Factor Ameliorates Acute Experimental Autoimmune Encephalomyelitis by Impairing the Homing of Encephalitogenic T Cells to the Central Nervous System

“…The migration of autoreactive T cells to sites of the autoimmune attack is critically dependent on the interaction of adhesion molecules on these cells with their ligands such as VCAM-1, ICAM-1, CD31, and LFA-1 on tissues in the target organ (31)(32)(33)(34)(35). Thus, the delayed onset and reduced severity of EAE in anti-MIF-treated mice appeared to be the consequence of the decreased expression of VCAM-1 in the CNS.…”