Microbiology & Immunology - Research Publications

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Author: Brooks, Andrew × Author: Kjer-Nielsen, Lars × Author: Purcell, Anthony × End date: 2008 × Start date: 2003 ×

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    A naturally selected dimorphism within the HLA-B44 supertype alters class I structure, peptide repertoire, and T cell recognition
    Macdonald, WA ; Purcell, AW ; Misfud, NA ; Ely, LK ; Williams, DS ; Chang, LN ; Gorman, J ; Clements, CS ; Kjer-Nielsen, L ; Koelle, DM ; Burrows, SR ; Tait, BD ; Holdsworth, R ; Brooks, AG ; Lovrecz, GO ; Lu, L ; Rossjohn, J ; McCluskey, J (ROCKEFELLER UNIV PRESS, 2003-09-01)
    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.
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    Natural HLA class 1 polymorphism controls the pathway of antigen presentation and susceptibility to viral evasion
    Zernich, D ; Purcell, AW ; Macdonald, WA ; Kjer-Nielsen, L ; Ely, LK ; Laham, N ; Crockford, T ; Mifsud, NA ; Bharadwaj, M ; Chang, L ; Tait, BD ; Holdsworth, R ; Brooks, AG ; Bottomley, SP ; Beddoe, T ; Peh, CA ; Rossjohn, J ; McCluskey, J (ROCKEFELLER UNIV PRESS, 2004-07-05)
    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.