Distinct assembly profiles of HLA-B molecules

• Published in: The Journal of immunology (1950) Vol. 192; no. 11; pp. 4967 - 4976
• Main Authors: Rizvi, Syed Monem, Salam, Nasir, Geng, Jie, Qi, Ying, Bream, Jay H, Duggal, Priya, Hussain, Shehnaz K, Martinson, Jeremy, Wolinsky, Steven M, Carrington, Mary, Raghavan, Malini
• Format: Journal Article
• Language: English
• Published: United States 01.06.2014
• Subjects: Acquired Immunodeficiency Syndrome - genetics; Acquired Immunodeficiency Syndrome - immunology; Antigen Presentation; Antigens - genetics; Antigens - immunology; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; Genetic Loci - immunology; HIV-1 - genetics; HIV-1 - immunology; HLA-B Antigens - genetics; HLA-B Antigens - immunology; Humans; Membrane Transport Proteins - genetics; Membrane Transport Proteins - immunology; Peptides - genetics; Peptides - immunology; Polymorphism, Genetic - genetics; Polymorphism, Genetic - immunology; Protein Folding
• ISSN: 0022-1767; 1550-6606; 1550-6606
• DOI: 10.4049/jimmunol.1301670

MHC class I polymorphisms are known to influence outcomes in a number of infectious diseases, cancers, and inflammatory diseases. Human MHC class I H chains are encoded by the HLA-A, HLA-B, and HLA-C genes. These genes are highly polymorphic, with the HLA-B locus being the most variable. Each HLA class I protein binds to a distinct set of peptide Ags, which are presented to CD8(+) T cells. HLA-disease associations have been shown in some cases to link to the peptide-binding characteristics of individual HLA class I molecules. In this study, we show that polymorphisms at the HLA-B locus profoundly influence the assembly characteristics of HLA-B molecules and the stabilities of their peptide-deficient forms. In particular, dependence on the assembly factor tapasin is highly variable, with frequent occurrence of strongly tapasin-dependent or independent allotypes. Several polymorphic HLA-B residues located near the C-terminal end of the peptide are key determinants of tapasin-independent assembly. In vitro refolded forms of tapasin-independent allotypes assemble more readily with peptides compared to tapasin-dependent allotypes that belong to the same supertype, and, during refolding, reduced aggregation of tapasin-independent allotypes is observed. Paradoxically, in HIV-infected individuals, greater tapasin-independent HLA-B assembly confers more rapid progression to death, consistent with previous findings that some HLA-B allotypes shown to be tapasin independent are associated with rapid progression to multiple AIDS outcomes. Together, these findings demonstrate significant variations in the assembly of HLA-B molecules and indicate influences of HLA-B-folding patterns upon infectious disease outcomes.