A naturally selected dimorphism within the HLA-B44 supertype alters class I structure, peptide repertoire, and T cell recognition.
HLA-B*4402 and B*4403 are naturally occurring MHC class I alleles that are both found at a high frequency in all human populations, and yet they only differ by one residue on the alpha2 helix (B*4402 Asp156-->B*4403 Leu156). CTLs discriminate between HLA-B*4402 and B*4403, and these allotypes stimulate strong mutual allogeneic responses reflecting their known barrier to hemopoeitic stem cell transplantation. Although HLA-B*4402 and B*4403 share >95% of their peptide repertoire, B*4403 presents more unique peptides than B*4402, consistent with the stronger T cell alloreactivity observed toward B*4403 compared with B*4402. Crystal structures of B*4402 and B*4403 show how the polymorphism at position 156 is completely buried and yet alters both the peptide and the heavy chain conformation, relaxing ligand selection by B*4403 compared with B*4402. Thus, the polymorphism between HLA-B*4402 and B*4403 modifies both peptide repertoire and T cell recognition, and is reflected in the paradoxically powerful alloreactivity that occurs across this "minimal" mismatch. The findings suggest that these closely related class I genes are maintained in diverse human populations through their differential impact on the selection of peptide ligands and the T cell repertoire.
Macdonald
Whitney A
WA
Dept. of Microbiology and Immunology, The University of Melbourne, Parkville, Victoria 3010, Australia.
Purcell
Anthony W
AW
Mifsud
Nicole A
NA
Ely
Lauren K
LK
Williams
David S
DS
Chang
Linus
L
Gorman
Jeffrey J
JJ
Clements
Craig S
CS
Kjer-Nielsen
Lars
L
Koelle
David M
DM
Burrows
Scott R
SR
Tait
Brian D
BD
Holdsworth
Rhonda
R
Brooks
Andrew G
AG
Lovrecz
George O
GO
Lu
Louis
L
Rossjohn
Jamie
J
McCluskey
James
J
D000483:Alleles; D002460:Cell Line; D018360:Crystallography, X-Ray; D016207:Cytokines / Q000097:blood; D005787:Gene Frequency; D015235:HLA-B Antigens / Q000737:chemistry / Q000235:genetics*; D059948:HLA-B44 Antigen; D006801:Humans; D007959:Lymphocyte Culture Test, Mixed; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D012727:Sex Characteristics; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013601:T-Lymphocytes / Q000276:immunology*
D016207:Cytokines; D015235:HLA-B Antigens; D059948:HLA-B44 Antigen