Trafficking of immune cells in the central nervous system

Abstract

The CNS is an immune-privileged environment, yet the local control of multiple pathogens is dependent on the ability of immune cells to access and operate within this site. However, inflammation of the distinct anatomical sites (i.e., meninges, cerebrospinal fluid, and parenchyma) associated with the CNS can also be deleterious. Therefore, control of lymphocyte entry and migration within the brain is vital to regulate protective and pathological responses. In this review, several recent advances are highlighted that provide new insights into the processes that regulate leukocyte access to, and movement within, the brain.

Figure 1. The structure of the brain and routes of leukocyte entry.

Beneath the skull lie three membranes that enclose the parenchyma of the brain: the dura mater, the arachnoid membrane, and the pia mater. The latter two enclose the subarachnoid space. (i) Leukocytes can enter across the choroid plexus, where CSF is produced by the choroid plexus epithelium in the ventricles. CSF containing leukocytes then enters the subarachnoid space, circulates around the brain, and (ii) exits via the venous sinus to be resorbed by the blood via the arachnoid villi. (iii) Blood supply to the brain enters in the subarachnoid space over the pia mater, generating the perivascular space (or Virchow-Robin space). Main arterial branches divide into capillaries, which terminate deep within the brain, supplying the parenchyma with blood. Leukocytes can potentially enter from the blood (iii), which requires them to cross the tightly regulated vascular endothelium (i.e., the BBB: the glia limitans, the subarachnoid space, and the pia mater). Cells can adhere to the endothelium and arrest at any point during this process.

Figure 2. Immune surveillance via the choroid plexus.

The choroid plexus is composed of highly invaginated loops of capillaries and pia mater that reach into the ventricles of the brain. Cells from the blood and under the influence of chemokines undergo adhesion, rolling, and diapedesis across the fenestrated capillary endothelium and pia mater of the choroid plexus. The basement membrane and tight junctions of the choroid plexus epithelium provide a further barrier, the brain-CSF barrier. These modified epithelial cells (Kolmer cells) have bulbous microvilli that secrete the CSF. Infiltrating leukocytes migrating through these cells enter the ventricles that contain CSF and circulate around the CNS. The chemokine CCL20 is expressed on the basolateral side of the choroid plexus epithelial cells, attracting CCR6-expressing CD4⁺ T cells. Chemokines and their receptors demonstrated to be involved in the trafficking of immune cells into the CSF are provided in Table 2.

Figure 3. Leukocyte trafficking across the glia limitans into the parenchyma of the brain.

Activated leukocytes expressing adhesion molecules and integrins roll and attach to the vascular endothelium. Successful diapedesis requires appropriate ligation of adhesion molecules, selectins, and integrins, signaling to both the infiltrating leukocyte and the brain endothelium. Expression of CXCL12 on the basolateral surface of endothelial cells recruits CXCR4⁺ T cells. However, retention of cells in the perivascular space occurs in the presence of high concentrations of CXCL10. Continued migration puts cells in contact with the glia limitans, which is composed of a highly structured wall of astrocytes. Further positive migratory signals, including chemokines, from these and surrounding cells may allow leukocyte migration into the parenchyma.