Murine cytomegalovirus downregulates ERAAP &amp; induces an unconventional T cell response to self

Geiger, Kristina; Manoharan, Michael; Coombs, Rachel; Park, Chan-Su; Lee, Angus; Shastri, Nilabh; Robey, Ellen A

doi:10.1101/2022.08.23.504566

Cited by 3 publications

(7 citation statements)

References 71 publications

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“…ERAAP dsRed is expressed and properly localized to the ER Our lab recently described that cells infected with MCMV express low levels of ERAAP 16 . Through this work, we became interested in identifying the cellular pathways that regulate ERAAP protein levels in cells under normal conditions and determine whether these pathways could be targeted during viral infection.…”

Section: Resultsmentioning

confidence: 99%

“…To avoid detection by CD8 + T-cells, viruses have evolved a myriad of immune evasion mechanisms aimed at preventing the presentation of antigenic peptides 2,13 . Interfering with ERAAP likely represents another one of these strategies as illustrated by HCMV, and likely MCMV [14][15][16] . Furthermore, a recent study by Stamatakis, et al, showed that ERAP generates potentially immunogenic SARS-CoV-2 S-derived peptides predicted to bind MHC 37 .…”

Section: Discussionmentioning

confidence: 99%

“…MCMV-induced ERAAP loss results in the presentation of the self-peptide FL9 in the MHC-I molecule Qa1b, the activating ligand of QFL T-cells. In infected mice, QFL T-cells are activated, produce inflammatory cytokines, and can kill cells experiencing ERAAP loss 16 . This exciting observation suggests that ERAAP dysregulation during infection has the potential to be sensed by the immune system.…”

Section: Discussionmentioning

confidence: 99%

“…Human cytomegalovirus (HCMV) encodes two micro RNAs, miR-UL112-5p and miR-US4-1, that target ERAP1 for degradation and this reduces the production of HCMV antigenic peptides 14,15 . Recently, our group showed that infection with mouse cytomegalovirus (MCMV) also results in ERAAP downregulation 16 . Interestingly, loss of ERAAP during MCMV infection triggers a QFL T-cell response.…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, loss of ERAAP during MCMV infection triggers a QFL T-cell response. In MCMV-infected mice, QFLs proliferate, produce inflammatory cytokines, and contribute to viral restriction 16 . In naïve mice, QFL T-cells have an antigen experienced phenotype 17,18 suggesting that actively surveying ERAAP dysfunction, and by extension the integrity of the APP, is an important aspect of immune surveillance.…”

Section: Introductionmentioning

confidence: 99%

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SARS-CoV-2 Envelope-mediated Golgi pH dysregulation interferes with ERAAP retention in cells

Vargas-Zapata

Geiger

Tran

et al. 2022

Preprint

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Endoplasmic reticulum (ER) aminopeptidase associated with antigen processing (ERAAP) trims peptide precursors in the ER for presentation by major histocompatibility (MHC)–I molecules to surveying CD8+T–cells. This function allows ERAAP to regulate the nature and quality of the peptide repertoire and, accordingly, the resulting immune responses. We recently showed that infection with murine cytomegalovirus leads to a dramatic loss of ERAAP levels in infected cells. In mice, this loss is associated with the activation of QFL T–cells, a subset of T–cells that monitor ERAAP integrity and eliminate cells experiencing ERAAP dysfunction. In this study, we aimed to identify host factors that regulate ERAAP expression level and determine whether these could be manipulated during viral infections. We performed a CRISPR knockout screen and identified ERp44 as a factor promoting ERAAP retention in the ER. ERp44′s interaction with ERAAP is dependent on the pH gradient between the ER and Golgi. We hypothesized that viruses that disrupt the pH of the secretory pathway interfere with ERAAP retention. Here, we demonstrate that expression of the Envelope (E) protein from Severe Acute Respiratory Syndrome Coronavirus 2 (SARS–CoV–2) leads to Golgi pH neutralization and consequently decrease of ERAAP intracellular levels. Furthermore, SARS–CoV–2–induced ERAAP loss correlates with its release into the extracellular environment. ERAAP′s reliance on ERp44 and a functioning ER/Golgi pH gradient for proper localization and function led us to propose that ERAAP serves as a sensor of disturbances in the secretory pathway during infection and disease.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

SARS-CoV-2 Envelope-mediated Golgi pH dysregulation interferes with ERAAP retention in cells

Vargas-Zapata

Geiger

Tran

et al. 2022

Preprint

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The promiscuous development of an unconventional Qa1^b-restricted T cell population

Valerio

Arana

Guan

et al. 2022

Preprint

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MHC-E restricted CD8 T cells show promise in vaccine settings, but their development and specificity remains poorly understood. Here we focus on a CD8 T cell population reactive to a self-peptide (FL9) bound to mouse MHC-E (Qa-1b) that is presented in response to loss of the MHC I processing enzyme ERAAP, termed QFL T cells. We find that mature QFL thymocytes are predominantly CD8ab+CD4-, show signs of agonist selection, and give rise to both CD8aa and CD8ab intraepithelial lymphocytes (IEL), as well as memory phenotype CD8ab T cells. QFL T cells require the MHC I subunit b-2 microglobulin (b2m), but do not require Qa1b or classical MHC I for positive selection. However, QFL thymocytes do require Qa1b for agonist selection and full functionality. Our data highlight the relaxed requirements for positive selection of an MHC-E restricted T cell population and suggest a CD8ab+CD4- pathway for development of CD8aa IELs.

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The promiscuous development of an unconventional Qa1b-restricted T cell population

Manoharan Valerio,

Arana,

Guan

et al. 2023

Front. Immunol.

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MHC-E restricted CD8 T cells show promise in vaccine settings, but their development and specificity remain poorly understood. Here we focus on a CD8 T cell population reactive to a self-peptide (FL9) bound to mouse MHC-E (Qa-1b) that is presented in response to loss of the MHC I processing enzyme ERAAP, termed QFL T cells. We find that mature QFL thymocytes are predominantly CD8αβ+CD4-, show signs of agonist selection, and give rise to both CD8αα and CD8αβ intraepithelial lymphocytes (IEL), as well as memory phenotype CD8αβ T cells. QFL T cells require the MHC I subunit β-2 microglobulin (β2m), but do not require Qa1b or classical MHC I for positive selection. However, QFL thymocytes do require Qa1b for agonist selection and full functionality. Our data highlight the relaxed requirements for positive selection of an MHC-E restricted T cell population and suggest a CD8αβ+CD4- pathway for development of CD8αα IELs.

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Murine cytomegalovirus downregulates ERAAP & induces an unconventional T cell response to self

Cited by 3 publications

References 71 publications

SARS-CoV-2 Envelope-mediated Golgi pH dysregulation interferes with ERAAP retention in cells

SARS-CoV-2 Envelope-mediated Golgi pH dysregulation interferes with ERAAP retention in cells

The promiscuous development of an unconventional Qa1^b-restricted T cell population

The promiscuous development of an unconventional Qa1b-restricted T cell population

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