Figure 2

Migration of activated T cells into brain. Peripherally, naïve T cells (N) encounter APC that present peptides from aberrant, misfolded, or aggregated proteins associated with neuroinflammatory processes. Upon presentation of antigen and delivery of appropriate co-stimulatory signals by APC, naïve T cells recognizing the antigen/MHC complex via the TCR become activated (A) leading to upregulation of CAMs on the T cell surface. These receptors and ligands include, but are not limited to, integrins, MCAM, and PSGL-1. Similarly, at sites of neuronal injury and neuroinflammation, danger signals, pro-inflammatory cytokines, and chemokines induce upregulation of endothelial associated CAMs on the basolateral side of the blood brain barrier. Following upregulation of CAMs, activated T cells (such as pro-inflammatory, anti-inflammatory or regulatory T cells) enter the vasculature and begin the process of extravasation via either a trans- or para-cellular route. This migratory process occurs in a step-wise manner beginning with T cells loosely tethering to endothelial cells via the binding of T cell ligands to selectins, such as E-selectin and other CAMs, such as VCAM, ICAM, and laminin 411 on the luminal side of the endothelial cells. Loose tethering allows the cell to roll along the luminal side of the endothelium and interact with CAMs, pulling it closer to the endothelial cell layer to eventual capture. Upon clustering of receptors and ligands on T cell and endothelial cell surfaces, the T cell begins "crawling" across the endothelial surface until reaching an endothelial cell junction, which signals the initiation of extravasation. Transmigration proceeds, via a chemotactic gradient allowing antigen-specific T cells entrance to the brain. Once in the parenchyma, activated T cells recognize antigen presented by MHC, initiating the efferent response program of the T cells to deliver either effector or regulatory function that supports the respective neurodegenerative or neuroprotective outcome.