Multiple sclerosis: T-cell receptor expression in distinct brain regions

Abstract

Multiple sclerosis (MS) is an inflammatory demyelinating disease where T cells attack the brain and the spinal cord. It is known that often particular T-cell clones are expanded in the target tissue, but it is still unknown, whether identical T-cell clones are present at distinct anatomical sites, or whether the T-cell spectrum is locally diverse. Therefore we compared the T-cell receptor (TCR) repertoire in distinct lesions and normal-appearing white matter (NAWM) from post-mortem brains of four MS patients. We analysed 19 lesions (inactive demyelinated, 15; slowly expanding chronic, 3; active lesions, 1) and 5 NAWM regions. The TCR beta-chain repertoire was investigated by CDR3 spectratyping. For each anatomical site 325 semi-nested PCR reactions were performed. About 800 Vbeta-NDN-Jbeta combinations were sequenced. Each of the four patients had distinct T-cell clones that were present in more than two anatomically distinct regions. These clones were not restricted to lesions, but were also present in NAWM. Some clones were present in all investigated lesions, and additionally, in NAWM sites. A single T-cell clone was detected in nine different sites in one patient. None of the clones was shared among different patients. Thus, pervasive T-cell clones exist in distinct regions of MS brain, and these clones are 'private' (unique) to individual patients. Analysis of the hypervariable NDN region revealed 'silent' nucleotide exchanges, i.e. nucleotide exchanges that code for identical amino acids. Such silent nucleotide exchanges suggest that the corresponding T-cell clones were recruited and stimulated by particular antigens. To attribute some of the pervasive clones to particular T-cell subsets, we isolated individual CD8+ T cells from cryosections by laser microdissection and characterized their TCR by single-cell PCR. These experiments revealed that at least some of the pervasive T-cell clones belonged to the CD8+ compartment, supporting the pathogenic relevance of this T-cell subset.

Role of CD8 T cell subsets in the pathogenesis of multiple sclerosis

“…Moreover, CDR3 nucleotide sequences encoding TcRs isolated from different lesions of individual MS brains revealed silent nucleotide changes implying that distinct T cell clones with identical antigen-specificity can be detected within MS lesions [33]. This CDR3 spectratyping confirms that infiltration of CD8 T cells in the lesions is selective, rather than stochastic.…”

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].…”

Multiple sclerosis and the role of immune cells

“…Axonal damage is also present [61,62] , and the degree of this was associated with abundance of microglia and CD8 + T cells [63] . Clonally expanded CD8 + T cells are present usually at the lesion edge, as well as in the perivascular infiltrates, indicating a specific antigen response and also possibly responsible for damages to neurons through cell dependent cytotoxicity [64][65][66][67] . It was also demonstrated that clonal γδ T cells are present in MS lesions [68] .…”