Oligoclonal expansion of memory CD8+ T cells in cerebrospinal fluid from multiple sclerosis patients

Abstract

Multiple sclerosis is a chronic inflammatory demyelinating disease of the CNS. Although the aetiology of multiple sclerosis is still unknown, it is widely believed that T cells play a central role in its pathogenesis. To identify and characterize disease-relevant T cells, we analysed CD4+ and CD8+ T cells freshly isolated from the CSF and peripheral blood of 36 multiple sclerosis patients for their T-cell receptor variable beta (TCRBV) chain repertoire. In most patients, we found significant overexpression of individual TCRBV chains on CD8+ T cells from CSF compared with peripheral blood. In contrast, only a few multiple sclerosis patients showed differences between the two compartments in TCRBV expression on CD4+ T cells. The overexpression of specific TCRBV chains on CD8+ T cells was found to be stable over several months in selected patients and involved mainly T cells with a memory phenotype. In two patients studied, individual TCRBV chain overexpression was found to be caused by the expansion of T cell populations with identical or highly similar rearranged T-cell receptor beta- and alpha-chain sequences, which were not found among peripheral blood CD8+ T cells. Our findings demonstrate selective enrichment of memory CD8+ T cells in the CSF of multiple sclerosis patients, suggesting a role for these CD8+ T cells in the pathogenesis of multiple sclerosis. Our study provides a basis for future trials to identify disease-associated antigens and disease pathogenesis in multiple sclerosis.

Intrathecal immune responses to EBV in early MS

“…There is an oligoclonal expansion of CD8 1 T cells in the MS plaques [20,21] and CSF [22]. Additionally, there is an enrichment in highly differentiated CD8 1 T cells in the CSF of patients with early MS, suggesting that CD8 1 T cells are activated and antigen-driven early in the course of MS [23].…”

Identification of Epstein-Barr virus proteins as putative targets of the immune response in multiple sclerosis

“…These responses were mainly found in the CD8 + CD28 + population, which is most relevant for the control of latent infection of EBV (27,28). Since CD28 + memory cells are dominant in the CSF compartment in MS and other infectious diseases, it is conceivable to assume that this population of cells plays an important role in the CNS immune response (5,29,30).…”

“…Reactivation of the virus in infected B cells that are potent antigen-presenting cells may periodically boost an autoimmune response in the CNS that involves antibodies and HLA-class I restricted T cell responses. Indeed, CD8 + T cells dominate MS lesions and are more often clonotypic than CD4 + T cells in MS tissue and CSF (4,5). T cell cross-recognition between virus (e.g., EBV peptides) and myelin antigens was demonstrated on the cellular (46,47) and structural levels (48).…”

“…Although the cause of MS is still unknown, it is widely accepted that the acquired immune response plays a key role in disease onset and progression (2,3). Several findings suggest that the local immune response in the CNS is highly focused in MS. CD8 + T cells clonally accumulate at large numbers in the lesions and cerebrospinal fluid (CSF) of MS patients (4,5). B cells, which are found in the CNS compartment, display a limited heavy chain repertoire and also contain dominant clonotypes.…”

Gene therapy in autoimmune, demyelinating disease of the central nervous system

“…117,118 However, recently a CD8-mediated disease has been induced in which IFNg is proinflammatory. 119,120 In human MS, there is evidence for CD8 T-cell expansions within the CNS, 121,122 which is indicative of local immune activity and further studies are warranted in this area as it is important that the models reflect events occurring in human disease. Furthermore, inhibition of TNF activity has consistently demonstrated disease-ameliorating effects in EAE although disease worsening occurred following systemic TNF neutralization in MS. 29 This has also been observed in some EAE systems.…”