Human autoreactive CD4+ T cells from naive CD45RA+ and memory CD45RO+ subsets differ with respect to epitope specificity and functional antigen avidity.
T cells with specificity for self-Ags are normally present in the peripheral blood, and, upon activation, may target tissue Ags and become involved in the pathogenesis of autoimmune processes. In multiple sclerosis, a demyelinating disease of the CNS, it is postulated that inflammatory damage is initiated by CD4+ T cells reactive to myelin Ags. To investigate the potential naive vs memory origin of circulating myelin-reactive cells, we have generated myelin basic protein (MBP)- and tetanus toxoid-specific T cell clones from CD45RA+/RO- and CD45RO+/RA- CD4+ T cell subsets from the peripheral blood of multiple sclerosis patients and controls. Our results show that 1) the response to MBP, different from that to TT, predominantly emerges from the CD45RA+ subset; 2) the reactivity to immunodominant MBP epitopes mostly resides in the CD45RA+ subset; 3) in each individual, the recognition of single MBP epitopes is skewed to either subset, with no overlap in the Ag fine specificity; and 4) in spite of a lower expression of costimulatory and adhesion molecules, CD45RA+ subset-derived clones recognize epitopes with higher functional Ag avidity. These findings point to a central role of the naive CD45RA+ T cell subset as the source for immunodominant, potentially pathogenic effector CD4+ T cell responses in humans.
Muraro
P A
PA
Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Pette
M
M
Bielekova
B
B
McFarland
H F
HF
Martin
R
R
D000328:Adult; D001324:Autoantigens / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D002469:Cell Separation; D002999:Clone Cells; D016207:Cytokines / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism*; D005260:Female; D006801:Humans; D016056:Immunodominant Epitopes / Q000378:metabolism; D007156:Immunologic Memory; D007399:Interphase / Q000276:immunology; D019041:L-Selectin / Q000096:biosynthesis; D017493:Leukocyte Common Antigens / Q000096:biosynthesis* / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D004676:Myelin Basic Protein / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000096:biosynthesis
D001324:Autoantigens; D015815:Cell Adhesion Molecules; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; D004676:Myelin Basic Protein; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D019041:L-Selectin; D017493:Leukocyte Common Antigens