The role of CD8+ T cells in neuroinflammation has been partly overshadowed by work on CD4+ T cells, even though they sometimes are the predominant cell type. Indeed, some studies have demonstrated the induction of variants of EAE, using CD8+ T cell clones; however, these models are the exception to the general rule that activated CD4+ T cells are required to induce EAE (Mars et al., 2011). In some cases, CD8+ T cell clones are expanded in the cerebrospinal fluid (CSF) of MS patients, and such clones can persist for many years (Skulina et al., 2004). It has been argued that whereas CD4+T cells and macrophages cause demyelination and damage to oligodendrocytes, CD8+ cells could contribute to the subsequent damage to exposed axons or neurites (McFarland and Martin, 2007).

Tregs, identified by the transcription factor Foxp3 and high levels of the IL2 receptor CD25, are important in controlling tissue-specific autoimmunity and inflammation, particularly in the gut. They are thought to act by the release of anti-inflammatory cytokines including IL10, IL35 and TGFβ (Korn et al., 2007). More recently, a population of CD8+ Tregs producing TGFβ and (surprisingly) IFNγ have been shown to suppress EAE induced by myelin oligodendrocyte glycoprotein (MOG) in SJL mice (Chen et al., 2009).

These observations led to investigations of Tregs in MS. The incidence of Tregs in the blood and the CNS of MS patients appears to be similar to that found in controls, but there is some evidence that the functional activity of Tregs is lower in individuals with relapsing and remitting MS than in those with the progressive disease (Venken et al., 2006).

Oligoclonal antibodies (i.e. antibodies produced by a small number of B cell clones) are present in the CSF of patients in most infectious diseases of the CNS as well as in MS. Since serum antibodies are effectively excluded by the blood–brain barrier (BBB), this fact alone indicates that some B cells must be present in the brain. The clones represent a small subset of those present in the blood (Owens et al., 2001); however, these clones can be stable over many years, which is longer than the normal lifespan of a plasma cell. This implies that the CNS environment, in some way, allows clones of B lymphocytes to persist. One hypothesis that could explain the persistence of B cells is infection with Epstein–Barr virus (EBV), a recent candidate virus in MS. Although this is an attractive hypothesis, there is still debate regarding the presence of EBV in MS tissues (Lassmann et al., 2011).

B cells and plasma cells were first observed in the Virchow–Robin spaces around larger blood vessels in MS, which explains why they could be detected in the CSF. Although in infection the antibody is usually specific to the pathogen, the antibody targets in MS and other inflammatory conditions were often not identifiable. This led to discussion as to whether these antibodies were merely an epiphenomenon (i.e. random local antibody production, caused by a few persistent B cells that had entered the perivascular space). This has never been a wholly satisfactory explanation, because antigen is normally required to drive the differentiation of B cells to plasma cells and to maintain an antibody response over time. Moreover, antibody-producing cells do occur in early MS lesions (Henderson et al., 2009), and B cell depletion can alleviate relapses in MS (Hauser et al., 2008). In EAE it appears that small amounts of antibody are important in targeting macrophages against oligodendrocytes, regardless of the immunological target of the T cells. For example, EAE can be induced by an immune response against astrocyte S100B protein or neuronal antigens such as neurofilament light chain (NF-L) (Huizinga et al., 2007). However, myelin damage is clearly due to antibodies to oligodendrocytes, especially MOG (Smith et al., 2005). Consequently, antibody may be required to target the immune reaction even if neuroinflammation is primarily driven by Th1 and Th17 cells.

The level of leukocyte traffic through the CNS is normally low in the absence of neuroinflammation; hence, there are relatively few lymphocytes present in the normal CNS. Lymphocyte migration into the CNS involves binding to the endothelium following selectin-mediated rolling and subsequent chemokine-mediated integrin activation, leading to firm adhesion and transmigration across the BBB. Within the inflamed CNS, chemokines direct lymphocytes, expressing the appropriate chemokine receptors to sites of inflammation. Lymphocyte migration into the CNS takes place primarily across post-capillary venules, and this is reflected in the location of lymphocytes in the CNS, in perivascular cuffs as seen in MS pathology. The cuff is formed by tightly packed lymphocytes and monocytes in the space between the endothelium and the astrocyte foot-processes, effectively between the double basal lamina produced by the two cell types. Leukocytes are then able to break through the glia limitans barrier following secretion of matrix metalloproteinases (Agrawal et al., 2013) to enter the brain parenchyma.

Lymphocyte migration into the CNS is controlled, as in other tissues, by chemokines and adhesion molecules expressed on the luminal side of the brain endothelium (Male, 2012). These controls are tissue specific, so that the pattern of lymphocyte migration into the CNS, and hence the types of immune reaction that can occur, is constrained by these controls (Engelhardt and Ransohoff, 2005; Man et al., 2007). The BBB prevents the diffusion of chemokines from the CNS to the blood side of the endothelium, via the paracellular route. Additionally, resting brain endothelium has comparatively few caveolae and other transport vesicles, which limits movement of chemokines by transcytosis. This means that chemokines produced by the brain endothelium make a particularly large contribution to the control of lymphocyte migration into the tissue, by comparison with endothelium in other tissues.