High frequency of autoreactive myelin proteolipid protein-specific T cellsin the periphery of naive mice: Mechanisms of selection of the self-reactive repertoire

The autoreactive T cells that escape central tolerance and form the periphe ral self-reactive repertoire determine both susceptibility to autoimmune di sease and the epitope dominance of a specific autoantigen. SJL (H-2(s)) mic e are highly susceptible to the induction of experimental autoimmune enceph alomyelitis (EAE) with myelin proteolipid protein (PLP). The two major ence phalitogenic epitopes of PLP (PLP 139-151 and PLP 178-191) bind to IA(s) wi th similar affinity; however, the immune response to the PLP 139-151 epitop e is always dominant. The immunodominance of the PLP 139-151 epitope in SJL mice appears to be due to the presence of expanded numbers of T cells (fre quency of 1/20,000 CD4(+) cells) reactive to PLP 139-151 in the peripheral repertoire of naive mice. Neither the PLP autoantigen nor infectious enviro nmental agents appear to be responsible for this expanded repertoire, as en dogenous PLP 139-151 reactivity is found in both PLP-deficient and germ-fre e mice. The high frequency of PLP 139-151-reactive T cells in SJL mice is p artly due to lack of thymic deletion to PLP 139-151, as the DM20 isoform of PLP (which lacks residues 116-150) is more abundantly expressed in the thy mus than full-length PLP. Reexpression of PLP 139-151 in the embryonic thym us results in a significant reduction of PLP 139-151-reactive precursors in naive mice. Thus, escape from central tolerance, combined with peripheral expansion by cross-reactive antigen(s), ap pears to be responsible for the high frequency of PLP 139-151-reactive T cells.