Skip to main content

Main menu

  • Home
  • Articles
    • Current Issue
    • Next in The JI
    • Archive
    • Brief Reviews
    • Pillars of Immunology
    • Translating Immunology
    • Most Read
    • Top Downloads
    • Annual Meeting Abstracts
  • COVID-19/SARS/MERS Articles
  • Info
    • About the Journal
    • For Authors
    • Journal Policies
    • Influence Statement
    • For Advertisers
  • Editors
  • Submit
    • Submit a Manuscript
    • Instructions for Authors
    • Journal Policies
  • Subscribe
    • Journal Subscriptions
    • Email Alerts
    • RSS Feeds
    • ImmunoCasts
  • More
    • Most Read
    • Most Cited
    • ImmunoCasts
    • AAI Disclaimer
    • Feedback
    • Help
    • Accessibility Statement
  • Other Publications
    • American Association of Immunologists
    • ImmunoHorizons

User menu

  • Subscribe
  • Log in

Search

  • Advanced search
The Journal of Immunology
  • Other Publications
    • American Association of Immunologists
    • ImmunoHorizons
  • Subscribe
  • Log in
The Journal of Immunology

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Next in The JI
    • Archive
    • Brief Reviews
    • Pillars of Immunology
    • Translating Immunology
    • Most Read
    • Top Downloads
    • Annual Meeting Abstracts
  • COVID-19/SARS/MERS Articles
  • Info
    • About the Journal
    • For Authors
    • Journal Policies
    • Influence Statement
    • For Advertisers
  • Editors
  • Submit
    • Submit a Manuscript
    • Instructions for Authors
    • Journal Policies
  • Subscribe
    • Journal Subscriptions
    • Email Alerts
    • RSS Feeds
    • ImmunoCasts
  • More
    • Most Read
    • Most Cited
    • ImmunoCasts
    • AAI Disclaimer
    • Feedback
    • Help
    • Accessibility Statement
  • Follow The Journal of Immunology on Twitter
  • Follow The Journal of Immunology on RSS

Diversity Outbred Mice Reveal the Quantitative Trait Locus and Regulatory Cells of HER2 Immunity

Wei-Zen Wei, Heather M. Gibson, Jennifer B. Jacob, Jeffrey A. Frelinger, Jay A. Berzofsky, Hoyoung Maeng, Gregory Dyson, Joyce D. Reyes, Shari Pilon-Thomas, Stuart Ratner and Kuang-Chung Wei
J Immunol September 15, 2020, 205 (6) 1554-1563; DOI: https://doi.org/10.4049/jimmunol.2000466
Wei-Zen Wei
*Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Wei-Zen Wei
Heather M. Gibson
*Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Heather M. Gibson
Jennifer B. Jacob
*Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Jennifer B. Jacob
Jeffrey A. Frelinger
†Valley Fever Center of Excellence, Department of Immunobiology, University of Arizona, Tucson, AZ 85724;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jay A. Berzofsky
‡Vaccine Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892; and
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Jay A. Berzofsky
Hoyoung Maeng
‡Vaccine Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892; and
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Hoyoung Maeng
Gregory Dyson
*Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Joyce D. Reyes
*Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shari Pilon-Thomas
§Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stuart Ratner
*Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Stuart Ratner
Kuang-Chung Wei
*Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF + SI
  • PDF
Loading

Key Points

  • Diversity Outbred F1 HER2 transgenic mice recapitulate human genetic heterozygosity.

  • Quantitative trait locus analysis reveals regulators of HER2 immunization response.

  • MHC-IB–reactive NK cells promote immune activation, countering Treg suppression.

Visual Abstract

Figure1
  • Download figure
  • Open in new tab
  • Download powerpoint

Abstract

The genetic basis and mechanisms of disparate antitumor immune response was investigated in Diversity Outbred (DO) F1 mice that express human HER2. DO mouse stock samples nearly the entire genetic repertoire of the species. We crossed DO mice with syngeneic HER2 transgenic mice to study the genetics of an anti-self HER2 response in a healthy outbred population. Anti-HER2 IgG was induced by Ad/E2TM or naked pE2TM, both encoding HER2 extracellular and transmembrane domains. The response of DO F1 HER2 transgenic mice was remarkably variable. Still, immune sera inhibited HER2+ SKBR3 cell survival in a dose-dependent fashion. Using DO quantitative trait locus (QTL) analysis, we mapped the QTL that influences both total IgG and IgG2(a/b/c) Ab response to either Ad/E2TM or pE2TM. QTL from these four datasets identified a region in chromosome 17 that was responsible for regulating the response. A/J and NOD segments of genes in this region drove elevated HER2 Ig levels. This region is rich in MHC-IB genes, several of which interact with inhibitory receptors of NK cells. (B6xA/J)F1 and (B6xNOD)F1 HER2 transgenic mice received Ad/E2TM after NK cell depletion, and they produced less HER2 IgG, demonstrating positive regulatory function of NK cells. Depletion of regulatory T cells enhanced response. Using DO QTL analysis, we show that MHC-IB reactive NK cells exert positive influence on the immunity, countering negative regulation by regulatory T cells. This new, to our knowledge, DO F1 platform is a powerful tool for revealing novel immune regulatory mechanisms and for testing new interventional strategies.

Footnotes

  • This work was supported by National Cancer Institute Grant CA76340 (to W.-Z.W.) and the Herrick Endowment (to W.-Z.W.).

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article:

    Chr
    chromosome
    CV
    coefficient of variation
    DC
    dendritic cell
    DO
    Diversity Outbred
    GigaMUGA
    Giga Mouse Universal Genotyping Array
    LOD
    logarithm of odds
    QTL
    quantitative trait locus
    SC
    splenocyte
    SNP
    single-nucleotide polymorphism
    Tg
    transgenic
    Treg
    regulatory T cell.

  • Received April 29, 2020.
  • Accepted July 11, 2020.
  • Copyright © 2020 by The American Association of Immunologists, Inc.
View Full Text

Pay Per Article - You may access this article (from the computer you are currently using) for 1 day for US$37.50

Regain Access - You can regain access to a recent Pay per Article purchase if your access period has not yet expired.

Log in using your username and password

Forgot your user name or password?
PreviousNext
Back to top

In this issue

The Journal of Immunology: 205 (6)
The Journal of Immunology
Vol. 205, Issue 6
15 Sep 2020
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Advertising (PDF)
  • Back Matter (PDF)
  • Editorial Board (PDF)
  • Front Matter (PDF)
Print
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for your interest in spreading the word about The Journal of Immunology.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Diversity Outbred Mice Reveal the Quantitative Trait Locus and Regulatory Cells of HER2 Immunity
(Your Name) has forwarded a page to you from The Journal of Immunology
(Your Name) thought you would like to see this page from the The Journal of Immunology web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Diversity Outbred Mice Reveal the Quantitative Trait Locus and Regulatory Cells of HER2 Immunity
Wei-Zen Wei, Heather M. Gibson, Jennifer B. Jacob, Jeffrey A. Frelinger, Jay A. Berzofsky, Hoyoung Maeng, Gregory Dyson, Joyce D. Reyes, Shari Pilon-Thomas, Stuart Ratner, Kuang-Chung Wei
The Journal of Immunology September 15, 2020, 205 (6) 1554-1563; DOI: 10.4049/jimmunol.2000466

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Diversity Outbred Mice Reveal the Quantitative Trait Locus and Regulatory Cells of HER2 Immunity
Wei-Zen Wei, Heather M. Gibson, Jennifer B. Jacob, Jeffrey A. Frelinger, Jay A. Berzofsky, Hoyoung Maeng, Gregory Dyson, Joyce D. Reyes, Shari Pilon-Thomas, Stuart Ratner, Kuang-Chung Wei
The Journal of Immunology September 15, 2020, 205 (6) 1554-1563; DOI: 10.4049/jimmunol.2000466
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like

Jump to section

  • Article
    • Visual Abstract
    • Abstract
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Disclosures
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Sex-Biased Aging Effects on Ig Somatic Hypermutation Targeting
  • Functional Interactions of Common Allotypes of Rhesus Macaque FcγR2A and FcγR3A with Human and Macaque IgG Subclasses
  • Revisiting the Pig IGHC Gene Locus in Different Breeds Uncovers Nine Distinct IGHG Genes
Show more IMMUNOGENETICS

Similar Articles

Navigate

  • Home
  • Current Issue
  • Next in The JI
  • Archive
  • Brief Reviews
  • Pillars of Immunology
  • Translating Immunology

For Authors

  • Submit a Manuscript
  • Instructions for Authors
  • About the Journal
  • Journal Policies
  • Editors

General Information

  • Advertisers
  • Subscribers
  • Rights and Permissions
  • Accessibility Statement
  • Public Access
  • Privacy Policy
  • Disclaimer

Journal Services

  • Email Alerts
  • RSS Feeds
  • ImmunoCasts
  • Twitter

Copyright © 2021 by The American Association of Immunologists, Inc.

Print ISSN 0022-1767        Online ISSN 1550-6606