Constitutive presentation of dominant epitopes from endogenous naturally processed self-beta 2-microglobulin to class II-restricted T cells leads to self-tolerance

Abstract

The mouse beta 2-microglobulin (m beta 2-m) peptide corresponding to residues 25-40 binds to the MHC class II molecules I-Ad and I-Ed and is immunogenic in BALB/c beta 2-m-deficient but not in normal BALB/c mice. The self-m beta 2-m peptide 25-40 is presented by both I-Ad and I-Ed class II molecules as demonstrated by the activation of T cell hybridomas specific for this sequence obtained from beta 2-m knock-out mice. By analyzing the effect of N- and C-terminal truncations of m beta 2-m25-40 on binding to class II molecules and on activation of T cell hybridomas, the minimum epitopes recognized by I-Ad and I-Ed-restricted T cells are included within amino acid residues 26-39 and 24-36, respectively. Both sets of T hybridomas are also activated by the corresponding naturally processed self-epitope presented by APC from BALB/c mice and from other H-2d strains, irrespective of their Mls phenotype. Therefore, the sequence 25-40 contains dominant naturally processed self-epitopes of the mouse beta 2-m. Processing of endogenous m beta 2-m is sensitive to protease inhibitors and lysosomotropic amines, and is not caused by reuptake of shed or released protein. These results indicate that self-beta 2-m-peptide-MHC class II complexes derive from constitutive processing of the endogenous intracellular pool of m beta 2-m in an acidic endosomal compartment. Antigenic complexes between m beta 2-m peptides and I-Ad or I-Ed class II 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 mice.