Multiple sclerosis: Brain-infiltrating CD8⁺T cells persist as clonal expansions in the cerebrospinal fluid and blood

Abstract

We surveyed the T cell receptor repertoire in three separate compartments (brain, cerebrospinal fluid, and blood) of two multiple sclerosis patients who initially had diagnostic brain biopsies to clarify their unusual clinical presentation but were subsequently confirmed to have typical multiple sclerosis. One of the brain biopsy specimens had been previously investigated by microdissection and single-cell PCR to determine the clonal composition of brain-infiltrating T cells at the single-cell level. Using complementarity-determining region 3 spectratyping, we identified several identical, expanded CD8 ؉ (but not CD4 ؉ ) T cell clones in all three compartments. Some of the expanded CD8 ؉ T cells also occurred in sorted CD38 ؉ blood cells, suggesting that they were activated. Strikingly, some of the brain-infiltrating CD8 ؉ T cell clones persisted for >5 years in the cerebrospinal fluid and͞or blood and may thus contribute to the progression of the disease.

Blood-borne soluble protein antigen intensifies T cell activation in autoimmune CNS lesions and exacerbates clinical disease

“…It is known that at least CD8 ϩ T cell accumulate and persist as clonally expanded populations in MS brains (27,28). The specificity of these T cell clones, however, remains to be identified.…”

Reconstitution of paired T cell receptor α- and β-chains from microdissected single cells of human inflammatory tissues

“…Clonal expansions appear as distinct peaks of a defined CDR3 length above a Gaussian-like background of polyclonal cells. Candidate V␤-J␤ populations were reamplified and sequenced directly (9). These candidates were regarded as clonally expanded only if readable sequences were obtained.…”

“…In previous studies we successfully amplified TCR ␤-chains from individual, morphologically characterized, tissue-infiltrating T cells from brains of patients with multiple sclerosis and from muscles of patients with myositis (7)(8)(9). Although these studies provided insight into intralesional TCR ␤-chain repertoires, they did not allow the identification of complete TCR ␣␤-heterodimers expressed by tissue-infiltrating T cells because information on the coexpressed ␣-chains was lacking, a result of the very limited number of available anti-␣-chain antibodies and higher variability of ␣-chain genes (10,11).…”

Oligodendrocyte cell death in pathogenesis of multiple sclerosis: Protection of oligodendrocytes from apoptosis by complement

“…Cytotoxic MBP-specific CD8-positive T cells and MOG-reactive T cells (in an adoptive transfer model) induced severe EAE manifestations [19][20]. CD8-positive T cells are abundant in MS lesions and may be present in lesions, CSF, and blood for many years as the result of clonal expansion [21]. In aggressive disease Complement activation products are also important in myelin opsonization and uptake by macrophages through complement receptors.…”