Natural HLA class I polymorphism controls the pathway of antigen presentation and susceptibility to viral evasion.
HLA class I polymorphism creates diversity in epitope specificity and T cell repertoire. We show that HLA polymorphism also controls the choice of Ag presentation pathway. A single amino acid polymorphism that distinguishes HLA-B*4402 (Asp116) from B*4405 (Tyr116) permits B*4405 to constitutively acquire peptides without any detectable incorporation into the transporter associated with Ag presentation (TAP)-associated peptide loading complex even under conditions of extreme peptide starvation. This mode of peptide capture is less susceptible to viral interference than the conventional loading pathway used by HLA-B*4402 that involves assembly of class I molecules within the peptide loading complex. Thus, B*4402 and B*4405 are at opposite extremes of a natural spectrum in HLA class I dependence on the PLC for Ag presentation. These findings unveil a new layer of MHC polymorphism that affects the generic pathway of Ag loading, revealing an unsuspected evolutionary trade-off in selection for optimal HLA class I loading versus effective pathogen evasion.
Zernich
Danielle
D
Department of Microbiology and Immunology, The University of Melbourne, Parkville, Victoria 3010, Australia.
Purcell
Anthony W
AW
Macdonald
Whitney A
WA
Kjer-Nielsen
Lars
L
Ely
Lauren K
LK
Laham
Nihay
N
Crockford
Tanya
T
Mifsud
Nicole A
NA
Bharadwaj
Mandvi
M
Chang
Linus
L
Tait
Brian D
BD
Holdsworth
Rhonda
R
Brooks
Andrew G
AG
Bottomley
Stephen P
SP
Beddoe
Travis
T
Peh
Chen Au
CA
Rossjohn
Jamie
J
McCluskey
James
J
D000818:Animals; D017951:Antigen Presentation; D017920:Antiporters / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D018360:Crystallography, X-Ray; D004198:Disease Susceptibility; D005805:Genes, MHC Class I; D015235:HLA-B Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006561:Herpes Simplex; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism; D026901:Membrane Transport Proteins; D051379:Mice; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011110:Polymorphism, Genetic; D011487:Protein Conformation; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018139:Simplexvirus
D017920:Antiporters; D015235:HLA-B Antigens; D007136:Immunoglobulins; D026901:Membrane Transport Proteins; D010455:Peptides; D020033:Protein Isoforms; C107762:tapasin