Differential adhesion molecule requirements for immune surveillance and inflammatory recruitment

Activated CD4 Th1 lymphocytes can enter the brain in the absence of an infl ammatory focus. However, the molecular mediators that regulate this early m igration of lymphocytes into the brain have remained unclear. We hypothesiz ed that the entry of these 'pioneer' lymphocytes into the brain is regulate d by a set of molecular events that are distinct from those used once infla mmation has been established. Using cells fluorescently labelled with the l ipophilic dye DiI, myelin basic protein (MBP)-specific CD4 lymphocytes that expressed low or high levels of very late antigen-4 (VLA-4) and non-antige n-specific activated splenocytes homed to mouse brain in similar quantities 2 h after adoptive transfer. However, antigen specificity and VLA-4 expres sion 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 sele ctin was upregulated 2 h after adoptive transfer, but not at 48 h, Monoclon al antibody to P selectin, but not to VLA-4, inhibited early migration of h igh VLA-LL-expressing MBP-specific lymphocytes. These results suggest that early migration occurs independent of the lymphocyte integrin VLA-4 and end othelial VCAM, but does require increased surface expression of endothelial P selectin.