Structure of a Classical MHC Class I Molecule That Binds “Non-Classical” Ligands

The chicken MHC YF1*7.1 X-ray structures reveal that this protein binds lipids and thus represents a "hybrid" class I complex with features of classical as well as non-classical MHC molecules

Impaired Cell Surface Expression of HLA-B Antigens on Mesenchymal Stem Cells and Muscle Cell Progenitors

HLA class-I expression is weak in embryonic stem cells but increases rapidly during lineage progression. It is unknown whether all three classical HLA class-I antigens follow the same developmental program. In the present study, we investigated allele-specific expression of HLA-A, -B, and -C at the mRNA and protein levels on human mesenchymal stem cells from bone marrow and adipose tissue as well as striated muscle satellite cells and lymphocytes. Using multicolour flow cytometry, we found high cell surface expression of HLA-A on all stem cells and PBMC examined. Surprisingly, HLA-B was either undetectable or very weakly expressed on all stem cells protecting them from complement-dependent cytotoxicity (CDC) using relevant human anti-B and anti-Cw sera. IFNγ stimulation for 48–72 h was required to induce full HLA–B protein expression. Quantitative real-time RT-PCR showed that IFNγ induced a 9–42 fold increase of all six HLA-A,-B,-C gene transcripts. Interestingly, prior to stimulation, gene transcripts for all but two alleles were present in similar amounts suggesting that post-transcriptional mechanisms regulate the constitutive expression of HLA-A,-B, and -C. Locus-restricted expression of HLA-A, -B and -C challenges our current understanding of the function of these molecules as regulators of CD8+ T-cell and NK-cell function and should lead to further inquiries into their expression on other cell types

Metal triggered conformational reorientation of a self peptide bound to a disease associated HLA B 27 subtype

Conformational changes of major histocompatibility complex MHC antigens have the potential to be recognized by T cells and may arise from polymorphic variation of the MHC molecule, the binding of modifying ligands, or both. Here, we investigated whether metal ions could affect allele dependent structural variation of the two minimally distinct human leukocyte antigen HLA B 27 05 and HLA B 27 09 subtypes, which exhibit differential association with the rheumatic disease ankylosing spondylitis AS . We employed NMR spectroscopy and X ray crystallography coupled with ensemble refinement to study the AS associated HLA B 27 05 subtype and the AS nonassociated HLA B 27 09 in complex with the self peptide pVIPR RRKWRRWHL . Both techniques revealed that pVIPR exhibits a higher degree of flexibility when complexed with HLA B 27 05 than with HLA B 27 09. Furthermore, we found that the binding of the metal ion Cu2 or Ni2 , but not Mn2 , Zn2 , or Hg2 , affects the structure of a pVIPR bound HLA B 27 molecule in a subtype dependent manner. In HLA B 27 05, the metals triggered conformational reorientations of pVIPR, but no such structural changes were observed in the HLA B 27 09 subtype, with or without bound metal ion. These observations provide the first demonstration that not only major histocompatibility complex class II, but also class I, molecules can undergo metal ion induced conformational alterations. Our findings suggest that metals may have a role in triggering rheumatic diseases such as AS and also have implications for the molecular basis of metal induced hypersensitivities and allergie

Dual, HLA B27 subtype dependent conformation of a self peptide

The products of the human leukocyte antigen subtypes HLA B 2705 and HLA B 2709 differ only in residue 116 Asp vs. His within the peptide binding groove but are differentially associated with the autoimmune disease ankylosing spondylitis AS ; HLA B 2705 occurs in AS patients, whereas HLA B 2709 does not. The subtypes also generate differential T cell repertoires as exemplified by distinct T cell responses against the self peptide pVIPR RRKWRRWHL . The crystal structures described here show that pVIPR binds in an unprecedented dual conformation only to HLA B 2705 molecules. In one binding mode, peptide pArg5 forms a salt bridge to Asp 116, connected with drastically different interactions between peptide and heavy chain, contrasting with the second, conventional conformation, which is exclusively found in the case of B 2709. These subtype dependent differences in pVIPR binding link the emergence of dissimilar T cell repertoires in individuals with HLA B 2705 or HLA B 2709 to the buried Asp116 His116 polymorphism and provide novel insights into peptide presentation by major histocompatibility antigen