title: Natural HLA class I polymorphism controls the pathway of antigen presentation and susceptibility to viral evasion.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Danielle
authors.initials: D
authors.lastname: Zernich
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Purcell
authors.forename: Whitney A
authors.initials: WA
authors.lastname: Macdonald
authors.forename: Lars
authors.initials: L
authors.lastname: Kjer-Nielsen
authors.forename: Lauren K
authors.initials: LK
authors.lastname: Ely
authors.forename: Nihay
authors.initials: N
authors.lastname: Laham
authors.forename: Tanya
authors.initials: T
authors.lastname: Crockford
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Mifsud
authors.forename: Mandvi
authors.initials: M
authors.lastname: Bharadwaj
authors.forename: Linus
authors.initials: L
authors.lastname: Chang
authors.forename: Brian D
authors.initials: BD
authors.lastname: Tait
authors.forename: Rhonda
authors.initials: R
authors.lastname: Holdsworth
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Brooks
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Bottomley
authors.forename: Travis
authors.initials: T
authors.lastname: Beddoe
authors.forename: Chen Au
authors.initials: CA
authors.lastname: Peh
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
authors.forename: James
authors.initials: J
authors.lastname: McCluskey
mesh_terms: 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
chemical_list: D017920:Antiporters; D015235:HLA-B Antigens; D007136:Immunoglobulins; D026901:Membrane Transport Proteins; D010455:Peptides; D020033:Protein Isoforms; C107762:tapasin