The impact of HLA-B micropolymorphism outside primary peptide anchor pockets on the CTL response to CMV

Burrows, Jacqueline M., Wynn, Katherine K., Tynan, Fleur E., Archbold, Julia, Miles, John J., Bell, Melissa J., Brennan, Rebekah M., Walker, Susan, McCluskey, James, Rossjohn, Jamie, Khanna, Rajiv, and Burrows, Scott R. (2007) The impact of HLA-B micropolymorphism outside primary peptide anchor pockets on the CTL response to CMV. European Journal of Immunology, 37 (4). pp. 946-953.

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The factors controlling epitope selection in the T cell response to persistent viruses are not fully understood, and we have examined this issue in the context of four HLA-B*35-binding peptides from the pp65 antigen of human cytomegalovirus, two of which are previously undescribed. Striking differences in the hierarchy of immunodominance between these four epitopes were observed in healthy virus carriers expressing HLA-B*3501 versus B*3508, two HLA-B allotypes that differ by a single amino acid at position 156 (HLA-B*3501, ¹⁵⁶Leucine; HLA-B*3508, ¹⁵⁶Arginine) that projects from the α2 helix into the centre of the peptide-binding groove. While HLA-B*3501⁺ individuals responded most strongly to the ¹²³IPSINVHHY¹³¹ and ³⁶⁶HPTFTSQY³⁷³ epitopes, HLA-B*3508⁺ individuals responded preferentially to ¹⁰³CPSQEPMSIYVY¹¹⁴ and ¹⁸⁸FPTKDVAL¹⁹⁵. By comparing peptide-MHC association and disassociation rates with peptide immunogenicity, it was clear that dissociation rates correlate more closely with the hierarchy of immunodominance among the four pp65 peptides. These findings demonstrate that MHC micropolymorphism at positions outside the primary anchor residue binding pockets can have a major impact on determinant selection in antiviral T cell responses. Such influences may provide the evolutionary pressure that maintains closely related MHC molecules in diverse human populations.

Item ID: 45395
Item Type: Article (Research - C1)
ISSN: 1521-4141
Keywords: antigen presentation; cytotoxic T cells; epitopes; human; viral
Funders: Australian National Health and Medical Research Council (NHMRC), Australian Research Council (ARC)
Date Deposited: 07 Sep 2016 02:14
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110702 Applied Immunology (incl Antibody Engineering, Xenotransplantation and T-cell Therapies) @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920108 Immune System and Allergy @ 100%
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