CONSTITUTIVE PRESENTATION OF DOMINANT EPITOPES FROM ENDOGENOUS NATURALLY PROCESSED SELF-BETA(2)-MICROGLOBULIN TO CLASS II-RESTRICTED T-CELLS LEADS TO SELF-TOLERANCE

The mouse beta(2)-microglobulin (m beta(2)-m) peptide corresponding to residues 25-40 binds to the MHC class II molecules I-A(d) and I-E(d) and is immunogenic in BALB/c beta(2)-m-deficient but not in normal BAL B/c mice. The self-m beta(2)-m peptide 25-40 is presented by both I-A( d) and I-E(d) class II molecules as demonstrated by the activation of T cell hybridomas specific for this sequence obtained from beta(2)-m k nock-out mice. By analyzing the effect of N- and C-terminal truncation s of m beta(2)-m25-40 on binding to class II molecules and on activati on of T cell hybridomas, the minimum epitopes recognized by I-A(d) and I-E(d) -restricted T cells are included within amino acid residues 26 -39 and 24-36, respectively. Both sets of T hybridomas are also activa ted by the corresponding naturally processed self-epitope presented by APC from BALB/c mice and from other H-2(d) strains, irrespective of t heir Mls phenotype. Therefore, the sequence 25-40 contains dominant na turally processed self-epitopes of the mouse beta(2)-m. Processing of endogenous m beta(2)-m is sensitive to protease inhibitors and lysosom otropic amines, and is not caused by reuptake of shed or released prot ein. These results indicate that self-beta(2)-m-peptide-MHC class II c omplexes derive from constitutive processing of the endogenous intrace llular pool of m beta(2)-m in an acidic endosomal compartment. Antigen ic complexes between m beta(2)-m peptides and I-A(d) or I-E(d) class I I molecules are constitutively expressed by APC of different tissues, including the thymus, and they are able to induce T cell tolerance, as shown by the lack of T cell response to m beta(2)-m25-40 in BALB/c mi ce.