Although they have been correlated with various autoimmune diseases (87C90), their implication, especially in MS (32, 91, 92), remain elusive. antigen-specific cytotoxic CD8+ T cells, neurite breakage appeared in contact zones between CD8+ T cells and neurites. Confocal live imaging gave a clear image of this process. Axonal transection has also been suggested in MS (30). Indeed, axonal injury, in 88 brain biopsy samples from 42 patients, correlated with the number of CD8+ T cells, but not CD3+ T cells, found in the lesions (31). Variable proportions of lesion-infiltrating CD8+ T cells express granzyme B [Physique ?[Physique1,1, personal results from Ref. (21)] and interferon (IFN), further evincing the ability of these cells to damage the CNS (21, 25, 32). In conclusion, CD8+ T cells seem more likely than CD4+ T cells to mediate CNS damage, in particular through their cytotoxic and proinflammatory properties. Open in a separate window Physique 1 Infiltrating T cells are mainly CD8+ T cells and express GZM-B. Example of staining with DAPI (blue), CD3 (reddish), CD8 (gray), and GZM-B (green). The collection in the pictures indicates 20?m. Stars show CD3+CD8+GZM-B+ and arrows show CD3+CD8?GZM-B? cells. GZM-B: granzyme-B. From personal data. Pathogenic CD8+ T Cells in the CSF Deciphering the mechanisms involved in MS development is made difficult by the limited access to the CNS compartment. As such, a lot of studies focus on the cerebrospinal fluid (CSF) as a surrogate compartment for understanding the T cell processes occurring migration through a model of the bloodCbrain barrier, especially those generating granzyme B, perforin, IFN, and interleukin 17 (IL-17). This was further confirmed in a mouse experimental autoimmune encephalomyelitis (EAE) model (25). Another Diosmin study found that granzyme A and B levels were higher in the CSF of patients in flare up, compared to those in clinical remission and control patients (34). Altogether, Diosmin these results suggest a specific enrichment of effector memory CD8+ T cells in the CNS compartment in MS and place them as disease effectors. CD8+ T Cell Migration into the Brain Studying the mechanisms leading to CD8+ T cell transmigration into the CNS further highlights their involvement in the disease process. Blockade of 4 integrin in EAE mice immunized with myelin oligodendrocyte glycoprotein (MOG)35C55 yields a decreased quantity of infiltrating CD8+ T cells, together with a reduced EAE score. However, a similar effect has been described for CD4+ T cells (25). More recently, melanoma cell adhesion molecule (MCAM), expressed by a subset of human effector CD8+ T cells, was reported to be upregulated during MS relapse compared to controls (35). Interestingly, MCAM blockade prevents the transmigration of human CD8+ T cells across a bloodCbrain barrier (BBB) model and decreases Diosmin the EAE score in active, transfer and spontaneous models (36C38). As MCAM binds itself and laminin 411 (37), which are both expressed by endothelial cells, Diosmin the mode of action of MCAM blockade is not yet known (35). P-glycoprotein (also known as multidrug resistance protein 1), a transporter involved in drug efflux (39) and in cytokine/chemokine secretion (40), has also been shown to be important for the trafficking of CD8+ T cells into the brain during the disease. Indeed, Mdr1a/b KO mice show significantly reduced EAE (40). In another Diosmin study, P-glycoprotein silencing led to decreased CD8 infiltration into the brain, with no effect on CD4+ T cells (41). P-glycoprotein control of endothelial CCC chemokine ligand 2 (CCL2) secretion was responsible for this result. Indeed, EAE mice lacking this protein or CCL2 show significantly reduced CD8+ migration into the brain. More significantly, CCL2 transcript has also been found to be elevated in six MS lesions compared to six controls (41). In conclusion, various studies on brain, spinal cord, and CSF, as well as around the mechanisms allowing T cell access into the brain highlight CD8+ T cells potential role in the development of MS. CD8+ T Cell Repertoire and Reactivity in MS A number of studies have focused on the T cell pools that arise with MS in order to understand their role in its pathophysiology. Different CNS and non-CNS antigens have been used to search for autoreactive T cells (3, 42), but to date the triggering antigen(s) is usually unknown. The search for a specific antigen is made SCKL1 more difficult because of the mechanisms of molecular mimicry, epitope distributing,.
Although they have been correlated with various autoimmune diseases (87C90), their implication, especially in MS (32, 91, 92), remain elusive