ERAP1 Controls the Interaction of the Inhibitory Receptor KIR3DL1 With HLA-B51:01 by Affecting Natural Killer Cell Function
The endoplasmic reticulum aminopeptidase ERAP1 regulates innate and adaptive immune responses by trimming peptides for presentation by major histocompatibility complex (MHC) class I molecules. Previously, we have shown that genetic or pharmacological inhibition of ERAP1 on murine and human tumor cel...
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Frontiers Media S.A.
2021
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oai:doaj.org-article:06850dcc2f5e4212b15a4f9dfffcba722021-12-01T18:14:18ZERAP1 Controls the Interaction of the Inhibitory Receptor KIR3DL1 With HLA-B51:01 by Affecting Natural Killer Cell Function1664-322410.3389/fimmu.2021.778103https://doaj.org/article/06850dcc2f5e4212b15a4f9dfffcba722021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.778103/fullhttps://doaj.org/toc/1664-3224The endoplasmic reticulum aminopeptidase ERAP1 regulates innate and adaptive immune responses by trimming peptides for presentation by major histocompatibility complex (MHC) class I molecules. Previously, we have shown that genetic or pharmacological inhibition of ERAP1 on murine and human tumor cell lines perturbs the engagement of NK cell inhibitory receptors Ly49C/I and Killer-cell Immunoglobulin-like receptors (KIRs), respectively, by their specific ligands (MHC class I molecules), thus leading to NK cell killing. However, the effect of ERAP1 inhibition in tumor cells was highly variable, suggesting that its efficacy may depend on several factors, including MHC class I typing. To identify MHC class I alleles and KIRs that are more sensitive to ERAP1 depletion, we stably silenced ERAP1 expression in human HLA class I-negative B lymphoblastoid cell line 721.221 (referred to as 221) transfected with a panel of KIR ligands (i.e. HLA-B*51:01, -Cw3, -Cw4 and -Cw7), or HLA-A2 which does not bind any KIR, and tested their ability to induce NK cell degranulation and cytotoxicity. No change in HLA class I surface expression was detected in all 221 transfectant cells after ERAP1 depletion. In contrast, CD107a expression levels were significantly increased on NK cells stimulated with 221-B*51:01 cells lacking ERAP1, particularly in the KIR3DL1-positive NK cell subset. Consistently, genetic or pharmacological inhibition of ERAP1 impaired the recognition of HLA-B*51:01 by the YTS NK cell overexpressing KIR3DL1*001, suggesting that ERAP1 inhibition renders HLA-B*51:01 molecules less eligible for binding to KIR3DL1. Overall, these results identify HLA-B*51:01/KIR3DL1 as one of the most susceptible combinations for ERAP1 inhibition, suggesting that individuals carrying HLA-B*51:01-like antigens may be candidates for immunotherapy based on pharmacological inhibition of ERAP1.Silvia D’AmicoValerio D’AlicandroMirco CompagnonePatrizia TemporaGiusy GuidaPaolo RomaniaValeria LucariniOmbretta MelaiuMichela FalcoMattia AlgeriDaniela PendeLoredana CifaldiLoredana CifaldiDoriana FruciFrontiers Media S.A.articleERAP1NK cellsNK cell immunotherapyHLA class IKIRcancerImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021) |
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DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
ERAP1 NK cells NK cell immunotherapy HLA class I KIR cancer Immunologic diseases. Allergy RC581-607 |
| spellingShingle |
ERAP1 NK cells NK cell immunotherapy HLA class I KIR cancer Immunologic diseases. Allergy RC581-607 Silvia D’Amico Valerio D’Alicandro Mirco Compagnone Patrizia Tempora Giusy Guida Paolo Romania Valeria Lucarini Ombretta Melaiu Michela Falco Mattia Algeri Daniela Pende Loredana Cifaldi Loredana Cifaldi Doriana Fruci ERAP1 Controls the Interaction of the Inhibitory Receptor KIR3DL1 With HLA-B51:01 by Affecting Natural Killer Cell Function |
| description |
The endoplasmic reticulum aminopeptidase ERAP1 regulates innate and adaptive immune responses by trimming peptides for presentation by major histocompatibility complex (MHC) class I molecules. Previously, we have shown that genetic or pharmacological inhibition of ERAP1 on murine and human tumor cell lines perturbs the engagement of NK cell inhibitory receptors Ly49C/I and Killer-cell Immunoglobulin-like receptors (KIRs), respectively, by their specific ligands (MHC class I molecules), thus leading to NK cell killing. However, the effect of ERAP1 inhibition in tumor cells was highly variable, suggesting that its efficacy may depend on several factors, including MHC class I typing. To identify MHC class I alleles and KIRs that are more sensitive to ERAP1 depletion, we stably silenced ERAP1 expression in human HLA class I-negative B lymphoblastoid cell line 721.221 (referred to as 221) transfected with a panel of KIR ligands (i.e. HLA-B*51:01, -Cw3, -Cw4 and -Cw7), or HLA-A2 which does not bind any KIR, and tested their ability to induce NK cell degranulation and cytotoxicity. No change in HLA class I surface expression was detected in all 221 transfectant cells after ERAP1 depletion. In contrast, CD107a expression levels were significantly increased on NK cells stimulated with 221-B*51:01 cells lacking ERAP1, particularly in the KIR3DL1-positive NK cell subset. Consistently, genetic or pharmacological inhibition of ERAP1 impaired the recognition of HLA-B*51:01 by the YTS NK cell overexpressing KIR3DL1*001, suggesting that ERAP1 inhibition renders HLA-B*51:01 molecules less eligible for binding to KIR3DL1. Overall, these results identify HLA-B*51:01/KIR3DL1 as one of the most susceptible combinations for ERAP1 inhibition, suggesting that individuals carrying HLA-B*51:01-like antigens may be candidates for immunotherapy based on pharmacological inhibition of ERAP1. |
| format |
article |
| author |
Silvia D’Amico Valerio D’Alicandro Mirco Compagnone Patrizia Tempora Giusy Guida Paolo Romania Valeria Lucarini Ombretta Melaiu Michela Falco Mattia Algeri Daniela Pende Loredana Cifaldi Loredana Cifaldi Doriana Fruci |
| author_facet |
Silvia D’Amico Valerio D’Alicandro Mirco Compagnone Patrizia Tempora Giusy Guida Paolo Romania Valeria Lucarini Ombretta Melaiu Michela Falco Mattia Algeri Daniela Pende Loredana Cifaldi Loredana Cifaldi Doriana Fruci |
| author_sort |
Silvia D’Amico |
| title |
ERAP1 Controls the Interaction of the Inhibitory Receptor KIR3DL1 With HLA-B51:01 by Affecting Natural Killer Cell Function |
| title_short |
ERAP1 Controls the Interaction of the Inhibitory Receptor KIR3DL1 With HLA-B51:01 by Affecting Natural Killer Cell Function |
| title_full |
ERAP1 Controls the Interaction of the Inhibitory Receptor KIR3DL1 With HLA-B51:01 by Affecting Natural Killer Cell Function |
| title_fullStr |
ERAP1 Controls the Interaction of the Inhibitory Receptor KIR3DL1 With HLA-B51:01 by Affecting Natural Killer Cell Function |
| title_full_unstemmed |
ERAP1 Controls the Interaction of the Inhibitory Receptor KIR3DL1 With HLA-B51:01 by Affecting Natural Killer Cell Function |
| title_sort |
erap1 controls the interaction of the inhibitory receptor kir3dl1 with hla-b51:01 by affecting natural killer cell function |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/06850dcc2f5e4212b15a4f9dfffcba72 |
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