Kinetics of abacavir-induced remodelling of the major histocompatibility complex class I peptide repertoire
Kinetics of abacavir-induced remodelling of the major histocompatibility complex class I peptide repertoire
Abacavir hypersensitivity syndrome can occur in individuals expressing the HLA-B*57:01 major histocompatibility complex class I allotype when utilising the drug abacavir as a part of their anti-retroviral regimen. The drug is known to bind within the HLA-B*57:01 antigen binding cleft, leading to the selection of novel self-peptide ligands, thus provoking life threatening immune responses. However, the sub-cellular location of abacavir binding and the mechanics of altered peptide selection are not well understood. Here, we probed the impact of abacavir on the assembly of HLA-B*57:01 peptide complexes. We show that whilst abacavir had minimal impact on the maturation or average stability of HLAB*57:01 molecules, abacavir was able to differentially enhance the formation, selectively decrease the dissociation, and alter tapasin loading dependency of certain HLA-B*57:01-peptide complexes. Our data reveals a spectrum of abacavir mediated effects on the immunopeptidome which reconciles the heterogeneous functional T cell data reported in the literature.
MHC I antigen presentation, T cells, abacavir, drug hypersensitivity, immunopeptidome, peptide selection, tapasin
Illing, Patricia
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van Hateren, Andy
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Darley, Rachel
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Croft, Nathan
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Mifsud, Nicole
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King, Samuel
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Kostenko, Lyudmila
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Bharadwaj, Mandvi
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McCluskey, James
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Elliott, Timothy
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Purcell, Anthony
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19 May 2021
Illing, Patricia
35d90e29-ef24-48c1-b4f2-cd1bb548e51b
van Hateren, Andy
e345fa3c-d89c-4b91-947e-c1d818cc7f71
Darley, Rachel
840a775a-867e-42ba-a7cb-d131c9fdb9c6
Croft, Nathan
6792a193-e691-4a26-a1ef-35012d7f00ec
Mifsud, Nicole
09fc6cb9-e6c4-460c-bf90-531c9e285bf5
King, Samuel
a3102fbf-6f85-432c-85e3-2eecac5e0511
Kostenko, Lyudmila
e1875855-a42e-446a-b0ac-8864b4146a42
Bharadwaj, Mandvi
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McCluskey, James
9c0fad9d-b56d-4c53-bedb-adf49943e74f
Elliott, Timothy
16670fa8-c2f9-477a-91df-7c9e5b453e0e
Purcell, Anthony
e2edc5f2-5d01-4421-ab72-b1e20ae1db70
Illing, Patricia, van Hateren, Andy, Darley, Rachel, Croft, Nathan, Mifsud, Nicole, King, Samuel, Kostenko, Lyudmila, Bharadwaj, Mandvi, McCluskey, James, Elliott, Timothy and Purcell, Anthony
(2021)
Kinetics of abacavir-induced remodelling of the major histocompatibility complex class I peptide repertoire.
Frontiers in Immunology, 12, [672737].
(doi:10.3389/fimmu.2021.672737).
Abstract
Abacavir hypersensitivity syndrome can occur in individuals expressing the HLA-B*57:01 major histocompatibility complex class I allotype when utilising the drug abacavir as a part of their anti-retroviral regimen. The drug is known to bind within the HLA-B*57:01 antigen binding cleft, leading to the selection of novel self-peptide ligands, thus provoking life threatening immune responses. However, the sub-cellular location of abacavir binding and the mechanics of altered peptide selection are not well understood. Here, we probed the impact of abacavir on the assembly of HLA-B*57:01 peptide complexes. We show that whilst abacavir had minimal impact on the maturation or average stability of HLAB*57:01 molecules, abacavir was able to differentially enhance the formation, selectively decrease the dissociation, and alter tapasin loading dependency of certain HLA-B*57:01-peptide complexes. Our data reveals a spectrum of abacavir mediated effects on the immunopeptidome which reconciles the heterogeneous functional T cell data reported in the literature.
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Accepted/In Press date: 26 April 2021
e-pub ahead of print date: 19 May 2021
Published date: 19 May 2021
Additional Information:
Funding Information:
This work was funded by the National Health and Medical Research Council Australia (NHMRC) Project grants 1122099 and 1165490 (awarded to AP) and by a Cancer Research UK programme grant C7056A and BBSRC project grant BB/ L010402/1 (both awarded to TE). PI was supported by a NHMRC Early Career Fellowship (1072159) and a Monash University Faculty of Medicine, Nursing and Health Sciences Senior Postdoctoral Fellowship. AP acknowledges salary support from a NHMRC Principal Research Fellowship (1137739).
Funding Information:
The authors acknowledge the provision of instrumentation, training and technical support by the Monash University Technology Research platforms; the Monash Biomedical Proteomics Facility and FlowCore. Computational resources were supported by the R@CMon/Monash Node of the NeCTAR Research Cloud, an initiative of the Australian Government’s Super Science Scheme and the Education Investment Fund. The authors thank Patrick Duriez and Leon Douglas of the Cancer Research UK Protein Production facility, as well as Nasia Kontouli, Hadil Said, Joe Morilla and Hana Ellingham for their help and technical expertise.
Publisher Copyright:
© Copyright © 2021 Illing, van Hateren, Darley, Croft, Mifsud, King, Kostenko, Bharadwaj, McCluskey, Elliott and Purcell.
Keywords:
MHC I antigen presentation, T cells, abacavir, drug hypersensitivity, immunopeptidome, peptide selection, tapasin
Identifiers
Local EPrints ID: 450797
URI: http://eprints.soton.ac.uk/id/eprint/450797
ISSN: 1664-3224
PURE UUID: 7ee9770e-2f25-4541-bd56-631da3c38821
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Date deposited: 12 Aug 2021 16:30
Last modified: 17 Mar 2024 03:08
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Author:
Patricia Illing
Author:
Rachel Darley
Author:
Nathan Croft
Author:
Nicole Mifsud
Author:
Samuel King
Author:
Lyudmila Kostenko
Author:
Mandvi Bharadwaj
Author:
James McCluskey
Author:
Anthony Purcell
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