Distinct assembly profiles of HLA-B molecules.
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.
Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109;
Syed Monem
SM
Rizvi
Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109;
Nasir
N
Salam
Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109;
Jie
J
Geng
Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD 21702; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139;
Ying
Y
Qi
Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205;
Jay H
JH
Bream
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205;
Priya
P
Duggal
Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, CA 90095; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048;
Shehnaz K
SK
Hussain
Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261; and.
Jeremy
J
Martinson
Division of Infectious Diseases, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Steven M
SM
Wolinsky
Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD 21702; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139;
Mary
M
Carrington
Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109; malinir@umich.edu.
Malini
M
Raghavan
D000163:Acquired Immunodeficiency Syndrome / Q000235:genetics / Q000276:immunology; D017951:Antigen Presentation; D000941:Antigens / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D056426:Genetic Loci / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology*; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics / Q000276:immunology; D010455:Peptides / Q000235:genetics / Q000276:immunology*; D011110:Polymorphism, Genetic / Q000235:genetics / Q000276:immunology; D017510:Protein Folding
D000941:Antigens; D015235:HLA-B Antigens; D026901:Membrane Transport Proteins; D010455:Peptides; C107762:tapasin