Low Constitutive Cell Surface Expression of HLA-B Is Caused by a Posttranslational Mechanism Involving Glu180 and Arg239

Christoffer Dellgren, Vanessa A. C. Ekwelum, Maria Ormhøj, Nicole Pallesen, Julie Knudsen, Jan O Nehlin, Torben Barington

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

HLA class I cell surface expression is crucial for normal immune responses, and variability in HLA expression may influence the course of infections. We have previously shown that classical HLA class I expression on many human cell types is biased with greatly reduced expression of HLA-B compared with HLA-A in the absence of inflammatory signals. In the search for the mechanisms responsible for this discrepancy, we have recently reported that the regulation is mainly posttranslational and that the C-terminal part of the α2 domain and the α3 domain contain the molecular determinants that explain most of the variability of expression between common HLA-A and -B allomorphs. In this study, we present a fine mapping of the structural determinants that allow such variability by exchanging key amino acids located within the C-terminal part of the α2 domain and the α3 domain of HLA-A2 and -B8, including Glu/Asp at position 177, Gln/Glu at position 180, Gly/Arg at position 239, and Pro/Ser at position 280. We found that the HLA-A2 and -B8 expression profiles could be interconverted to a large extent by mutual exchange of Gln/Glu at position 180 or by Gly/Arg at position 239. The presence of Gln(180) and Gly(239), as in HLA-A2, led to higher cell surface expression levels when compared with the presence of Glu(180) and Arg(239), as in HLA-B8. This indicates that the amino acids at positions 180 and 239 determine the level of cell surface expression of common HLA-A and -B allomorphs, probably by affecting HLA processing in the Ag presentation pathway.

OriginalsprogEngelsk
TidsskriftJournal of Immunology
Vol/bind197
Udgave nummer12
Sider (fra-til)4807-4816
ISSN0022-1767
DOI
StatusUdgivet - 2016

Fingeraftryk

HLA-B8 Antigen
HLA-A2 Antigen
Amino Acids
Viperidae

Citer dette

Dellgren, Christoffer ; Ekwelum, Vanessa A. C. ; Ormhøj, Maria ; Pallesen, Nicole ; Knudsen, Julie ; Nehlin, Jan O ; Barington, Torben. / Low Constitutive Cell Surface Expression of HLA-B Is Caused by a Posttranslational Mechanism Involving Glu180 and Arg239. I: Journal of Immunology. 2016 ; Bind 197, Nr. 12. s. 4807-4816.
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title = "Low Constitutive Cell Surface Expression of HLA-B Is Caused by a Posttranslational Mechanism Involving Glu180 and Arg239",
abstract = "HLA class I cell surface expression is crucial for normal immune responses, and variability in HLA expression may influence the course of infections. We have previously shown that classical HLA class I expression on many human cell types is biased with greatly reduced expression of HLA-B compared with HLA-A in the absence of inflammatory signals. In the search for the mechanisms responsible for this discrepancy, we have recently reported that the regulation is mainly posttranslational and that the C-terminal part of the α2 domain and the α3 domain contain the molecular determinants that explain most of the variability of expression between common HLA-A and -B allomorphs. In this study, we present a fine mapping of the structural determinants that allow such variability by exchanging key amino acids located within the C-terminal part of the α2 domain and the α3 domain of HLA-A2 and -B8, including Glu/Asp at position 177, Gln/Glu at position 180, Gly/Arg at position 239, and Pro/Ser at position 280. We found that the HLA-A2 and -B8 expression profiles could be interconverted to a large extent by mutual exchange of Gln/Glu at position 180 or by Gly/Arg at position 239. The presence of Gln(180) and Gly(239), as in HLA-A2, led to higher cell surface expression levels when compared with the presence of Glu(180) and Arg(239), as in HLA-B8. This indicates that the amino acids at positions 180 and 239 determine the level of cell surface expression of common HLA-A and -B allomorphs, probably by affecting HLA processing in the Ag presentation pathway.",
author = "Christoffer Dellgren and Ekwelum, {Vanessa A. C.} and Maria Ormh{\o}j and Nicole Pallesen and Julie Knudsen and Nehlin, {Jan O} and Torben Barington",
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Low Constitutive Cell Surface Expression of HLA-B Is Caused by a Posttranslational Mechanism Involving Glu180 and Arg239. / Dellgren, Christoffer; Ekwelum, Vanessa A. C. ; Ormhøj, Maria; Pallesen, Nicole; Knudsen, Julie; Nehlin, Jan O; Barington, Torben.

I: Journal of Immunology, Bind 197, Nr. 12, 2016, s. 4807-4816.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Low Constitutive Cell Surface Expression of HLA-B Is Caused by a Posttranslational Mechanism Involving Glu180 and Arg239

AU - Dellgren, Christoffer

AU - Ekwelum, Vanessa A. C.

AU - Ormhøj, Maria

AU - Pallesen, Nicole

AU - Knudsen, Julie

AU - Nehlin, Jan O

AU - Barington, Torben

N1 - Copyright © 2016 by The American Association of Immunologists, Inc.

PY - 2016

Y1 - 2016

N2 - HLA class I cell surface expression is crucial for normal immune responses, and variability in HLA expression may influence the course of infections. We have previously shown that classical HLA class I expression on many human cell types is biased with greatly reduced expression of HLA-B compared with HLA-A in the absence of inflammatory signals. In the search for the mechanisms responsible for this discrepancy, we have recently reported that the regulation is mainly posttranslational and that the C-terminal part of the α2 domain and the α3 domain contain the molecular determinants that explain most of the variability of expression between common HLA-A and -B allomorphs. In this study, we present a fine mapping of the structural determinants that allow such variability by exchanging key amino acids located within the C-terminal part of the α2 domain and the α3 domain of HLA-A2 and -B8, including Glu/Asp at position 177, Gln/Glu at position 180, Gly/Arg at position 239, and Pro/Ser at position 280. We found that the HLA-A2 and -B8 expression profiles could be interconverted to a large extent by mutual exchange of Gln/Glu at position 180 or by Gly/Arg at position 239. The presence of Gln(180) and Gly(239), as in HLA-A2, led to higher cell surface expression levels when compared with the presence of Glu(180) and Arg(239), as in HLA-B8. This indicates that the amino acids at positions 180 and 239 determine the level of cell surface expression of common HLA-A and -B allomorphs, probably by affecting HLA processing in the Ag presentation pathway.

AB - HLA class I cell surface expression is crucial for normal immune responses, and variability in HLA expression may influence the course of infections. We have previously shown that classical HLA class I expression on many human cell types is biased with greatly reduced expression of HLA-B compared with HLA-A in the absence of inflammatory signals. In the search for the mechanisms responsible for this discrepancy, we have recently reported that the regulation is mainly posttranslational and that the C-terminal part of the α2 domain and the α3 domain contain the molecular determinants that explain most of the variability of expression between common HLA-A and -B allomorphs. In this study, we present a fine mapping of the structural determinants that allow such variability by exchanging key amino acids located within the C-terminal part of the α2 domain and the α3 domain of HLA-A2 and -B8, including Glu/Asp at position 177, Gln/Glu at position 180, Gly/Arg at position 239, and Pro/Ser at position 280. We found that the HLA-A2 and -B8 expression profiles could be interconverted to a large extent by mutual exchange of Gln/Glu at position 180 or by Gly/Arg at position 239. The presence of Gln(180) and Gly(239), as in HLA-A2, led to higher cell surface expression levels when compared with the presence of Glu(180) and Arg(239), as in HLA-B8. This indicates that the amino acids at positions 180 and 239 determine the level of cell surface expression of common HLA-A and -B allomorphs, probably by affecting HLA processing in the Ag presentation pathway.

U2 - 10.4049/jimmunol.1502546

DO - 10.4049/jimmunol.1502546

M3 - Journal article

C2 - 27821669

VL - 197

SP - 4807

EP - 4816

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 12

ER -