Human autoreactive CD4(+) T cells from naive CD45RA(+) and memory CD45RO(+) subsets differ with respect to epitope specificity and functional antigenavidity

T cells with specificity for self-Ags are normally present in the periphera l blood, and, upon activation, may target tissue Ags and become involved in the pathogenesis of autoimmune processes. In multiple sclerosis, a demyeli nating disease of the CNS, it is postulated that inflammatory damage is ini tiated by CD4(+) T cells reactive to myelin Ags, To investigate the potenti al naive vs memory origin of circulating myelin-reactive cells, we have gen erated myelin basic protein (MBP)- and tetanus toroid-specific T cell clone s from CD45RA(+)/RO- and CD45RO(+)/RA(-) CD4(+) T cell subsets from the per ipheral blood of multiple sclerosis patients and controls. Our results show that 1) the response to MBP, different from that to TT, predominantly emer ges from the CD45RA(+) subset; 2) the reactivity to immunodominant MBP epit opes mostly resides in the CD45RA(+) subset; 3) in each individual, the rec ognition 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 costi mulatory and adhesion molecules, CD45RA(+) subset-derived clones recognize epitopes with higher functional Ag avidity. These findings point to a centr al role of the naive CD45RA(+) T cell subset as the source for immunodomina nt, potentially pathogenic effector CD4(+) T cell responses in humans.