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Published online on February 17, 2004, 10.1073/pnas.0308689100
PNAS | February 24, 2004 | vol. 101 | no. 8 | 2428-2433


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

Christian Skulina {dagger} {ddagger}, Stephan Schmidt §, Klaus Dornmair {dagger} {ddagger}, Holger Babbe ¶, Axel Roers ||, Klaus Rajewsky {dagger}{dagger}, Hartmut Wekerle {ddagger}, Reinhard Hohlfeld {dagger} {ddagger}, and Norbert Goebels {dagger} {ddagger} {ddagger}{ddagger}

{dagger}Institute for Clinical Neuroimmunology, Ludwig-Maximilians University, 81377 Munich, Germany; {ddagger}Max Planck Institute for Neurobiology, 82152 Martinsried, Germany; §Department of Neurology, University of Bonn, 53127 Bonn, Germany; Department of Genetics and {dagger}{dagger}CBR Institute for Biomedical Research, Harvard Medical School, Boston, MA 02115; and ||Department of Dermatology, University of Cologne, 50931 Cologne, Germany

Contributed by Klaus Rajewsky, December 29, 2003

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 and/or blood and may thus contribute to the progression of the disease.


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  		Table 2. TCR-BV sequences identified in brain tissue, CSF cells, and sorted peripheral blood cells (PBL) from Patient A by CDR3 spectratyping

 

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  		Table 3. TCR-BV sequences identified in brain tissue, CSF cells, and sorted peripheral blood cells (PBL) from patient B by CDR3 spectratyping

 
Abbreviations: TCR, T cell receptor; BV, V{beta}; BJ, J{beta}; BC, C{beta}; CSF, cerebrospinal fluid; CDR3, complementarity-determining region 3; MS, multiple sclerosis; PBMC, peripheral blood mononuclear cell.

Data deposition: Sequence data for TCR {beta}-chains in Tables 2 and 3 have been deposited in the GenBank database (accession nos. AY534307–AY534315).

{ddagger}{ddagger} To whom correspondence should be addressed: Department of Neurology, University Hospital Zurich, Frauenklinikstrasse 26, CH-8091 Zurich, Switzerland. E-mail: norbert.goebels{at}usz.ch.


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