Expansion and functional relevance of high-avidity myelin-specific CD4+ T cells in multiple sclerosis.
Multiple sclerosis (MS) is an autoimmune disease in which myelin-specific T cells are believed to play a crucial pathogenic role. Nevertheless, so far it has been extremely difficult to demonstrate differences in T cell reactivity to myelin Ag between MS patients and controls. We believe that by using unphysiologically high Ag concentrations previous studies have missed a highly relevant aspect of autoimmune responses, i.e., T cells recognizing Ag with high functional avidity. Therefore, we focused on the characterization of high-avidity myelin-specific CD4+ T cells in a large cohort of MS patients and controls that was matched demographically and with respect to expression of MHC class II alleles. We demonstrated that their frequency is significantly higher in MS patients while the numbers of control T cells specific for influenza hemagglutinin are virtually identical between the two cohorts; that high-avidity T cells are enriched for previously in vivo-activated cells and are significantly skewed toward a proinflammatory phenotype. Moreover, the immunodominant epitopes that were most discriminatory between MS patients and controls differed from those described previously and were clearly biased toward epitopes with lower predicted binding affinities to HLA-DR molecules, pointing at the importance of thymic selection for the generation of the autoimmune T cell repertoire. Correlations between selected immunological parameters and magnetic resonance imaging markers indicate that the specificity and function of these cells influences phenotypic disease expression. These data have important implications for autoimmunity research and should be considered in the development of Ag-specific therapies in MS.
Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Bibiana
B
Bielekova
Myong-Hee
MH
Sung
Nadja
N
Kadom
Richard
R
Simon
Henry
H
McFarland
Roland
R
Martin
D000328:Adult; D000368:Aged; D000483:Alleles; D000595:Amino Acid Sequence; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D002455:Cell Division / Q000276:immunology; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism*; D005260:Female; D015802:HLA-DR2 Antigen / Q000235:genetics / Q000378:metabolism; D015804:HLA-DR4 Antigen / Q000235:genetics / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007156:Immunologic Memory; D016130:Immunophenotyping; D015851:Interleukin-7 / Q000494:pharmacology; D007399:Interphase / Q000276:immunology; D018655:Lymphocyte Count; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000175:diagnosis / Q000235:genetics / Q000276:immunology*; D004676:Myelin Basic Protein / Q000276:immunology* / Q000378:metabolism*; D011237:Predictive Value of Tests; D011485:Protein Binding / Q000235:genetics / Q000276:immunology
D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D015802:HLA-DR2 Antigen; D015804:HLA-DR4 Antigen; D015851:Interleukin-7; D004676:Myelin Basic Protein