H2-M beta 1 and H2-M beta 2 heterodimers equally promote CLIP removal in I-A(q) molecules from autoimmune-prone DBA/1 mice

Antigen-presenting cells degrade endocytosed antigens, e.g. collagen type I I, into peptides that are bound and presented to arthritogenic CD4(+) helpe r T cells by major histocompatibility complex (MHC) class II molecules. Eff icient loading of many MHC class II alleles with peptides requires the assi stance of H2-M (HLA-DM in humans), a heterodimeric MHC class II-like molecu le that facilitates CLIP removal from MHC class II molecules and aids to sh ape the peptide repertoire presented by MHC class II to CD4(+) T cells. In contrast to the KLA-DM region in humans, the beta -chain locus is duplicate d in mice, with the H2-Mb1 beta-chain distal to H2-Mb2 and the H2-Ma alpha- chain gene. H2-M alleles appear to be associated with the development of au toimmune diseases. Recent data showed that M beta1 and M beta2 isoforms are differentially expressed in isolated macrophages and B cells, respectively . The tissue expression and functional role of these heterodimers in promot ing CLIP removal and peptide selection have not been addressed. We utilized the human T2 cell line, which lacks part of chromosome 6 encompassing the MHC class II and DM genes, to construct transgenic cell lines expressing th e MHC class II heterodimer I-A(q) alone or in the presence of H2-M alpha be ta1 or H2-M alpha beta2 heterodimers, Both H2-M isoforms facilitate the exc hange of CLIP for cognate peptides on I-Aq molecules from arthritis-suscept ible DBA/1 mice and induce a conformational change in I-A(q) molecules. Mor eover, I-A(q) cell-surface expression is not absolutely dependent on H2-M m olecules. These data suggest that I-A(q) exhibits a high affinity for CLIP since virtually all I-A(q) molecules on T2 cells were found to be associate d with CLIP in the absence of both H2-M isoforms.