Structural analysis of H2-Db class I molecules containing two different allelic forms of the type 1 diabetes susceptibility factor beta-2 microglobulin: implications for the mechanism underlying variations in antigen presentation.

Beta-2 microglobulin (beta2m) is a member of the immunoglobulin-like domain superfamily that is an essential structural subunit of the MHC class I (MHC-I) molecule. beta2m was previously identified as a susceptibility factor for the development of type 1 diabetes (T1D) in NOD mice, whereby transgenic expression of the beta2ma variant, but not the beta2mb variant, restored diabetes susceptibility to normally resistant NOD.beta2mnull mice.

How H13 histocompatibility peptides differing by a single methyl group and lacking conventional MHC binding anchor motifs determine self-nonself discrimination.

The mouse H13 minor histocompatibility (H) Ag, originally detected as a barrier to allograft transplants, is remarkable in that rejection is a consequence of an extremely subtle interchange, P4(Val/Ile), in a nonamer H2-D(b)-bound peptide. Moreover, H13 peptides lack the canonical P5(Asn) central anchor residue normally considered important for forming a peptide/MHC complex. To understand how these noncanonical peptide pMHC complexes form physiologically active TCR ligands, crystal structures of allelic H13 pD(b) complexes and a P5(Asn) anchored pD(b) analog were solved to high resolution.