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CD8⁺ T Cell-Mediated HLA-A*0201-Restricted Cytotoxicity to Transaldolase Peptide 168–176 in Patients with Multiple Sclerosis¹

Brian Niland^*,, Katalin Banki^*,, William E. Biddison and Andras Perl^2,*,

^* Department of Medicine, Department of Pathology, and Department of Microbiology and Immunology, State University of New York, College of Medicine, Syracuse, NY 13210; and Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892

Transaldolase (TAL) is expressed at selectively high levels in oligodendrocytes and targeted by autoreactive T cells of patients with multiple sclerosis (MS). Among 14 TAL peptides with predicted HLA-A2 binding, TAL 168–176 (LLFSFAQAV, TALpep) exhibited high affinity for HLA-A2. Prevalence of HLA-A2-restricted CD8⁺ T cells specific for TALpep was increased in PBMC of HLA-A2⁺ MS patients, as compared with HLA-A2^– MS patients, HLA-A2⁺ other neurological disease patients, and HLA-A2⁺ healthy donors. HLA-A*0201/TALpep tetramers detected increased frequency of TAL-specific CD8⁺ T cells, and precursor frequency of TAL-specific IFN--producing T cells was increased in each of seven HLA-A2⁺ MS patients tested. Stimulation by TALpep or rTAL of PBMC from HLA-A2⁺ MS patients elicited killing of TALpep-pulsed HLA-A2-transfected HmyA2.1 lymphoma cells, but not HLA-A3-transfected control HmyA3.1 targets. Without peptide pulsing of targets, HLA-A2-transfected, but not control MO3.13 oligodendroglial cells, expressing high levels of endogenous TAL, were also killed by CD8⁺ CTL of MS patients, indicating recognition of endogenously processed TAL. TCR V repertoire analysis revealed use of the TCR V14 gene by T cell lines (TCL) of MS patients generated via stimulation by TAL- or TALpep-pulsed APCs. All TAL-specific TCL-binding HLA-A*0201/TALpep tetramers expressed TCR V14 on the cell surface. Moreover, Ab to TCR V14 abrogated cytotoxicity by HLA-A2-restricted TAL-specific TCL. Therefore, TAL-specific CTL may serve as a novel target for therapeutic intervention in patients with MS.

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