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

Invariant NKT Cells Promote the Development of Highly Cytotoxic Multipotent CXCR3+CCR4+CD8+ T Cells That Mediate Rapid Hepatocyte Allograft Rejection

Jason M. Zimmerer, Bryce A. Ringwald, Sachi R. Chaudhari, Jing Han, Chelsea M. Peterson, Robert T. Warren, Madison M. Hart, Mahmoud Abdel-Rasoul and Ginny L. Bumgardner
J Immunol December 15, 2021, 207 (12) 3107-3121; DOI: https://doi.org/10.4049/jimmunol.2100334
Jason M. Zimmerer
*Comprehensive Transplant Center, Department of Surgery, The Ohio State University College of Medicine, Columbus, OH;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Bryce A. Ringwald
†Medical Student Research Program, The Ohio State University College of Medicine, Columbus, OH;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sachi R. Chaudhari
*Comprehensive Transplant Center, Department of Surgery, The Ohio State University College of Medicine, Columbus, OH;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Sachi R. Chaudhari
Jing Han
‡Biomedical Sciences Graduate Program, The Ohio State University College of Medicine, Columbus, OH; and
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Chelsea M. Peterson
*Comprehensive Transplant Center, Department of Surgery, The Ohio State University College of Medicine, Columbus, OH;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Robert T. Warren
*Comprehensive Transplant Center, Department of Surgery, The Ohio State University College of Medicine, Columbus, OH;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Robert T. Warren
Madison M. Hart
*Comprehensive Transplant Center, Department of Surgery, The Ohio State University College of Medicine, Columbus, OH;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mahmoud Abdel-Rasoul
§Center for Biostatistics, The Ohio State University, Columbus, OH
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Mahmoud Abdel-Rasoul
Ginny L. Bumgardner
*Comprehensive Transplant Center, Department of Surgery, The Ohio State University College of Medicine, Columbus, OH;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Ginny L. Bumgardner
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF + SI
  • PDF
Loading

Key Points

  • In vivo development of alloprimed CD8+ CTLs requires iNKT or CD4+ T cell help.

  • iNKTs promote the in vivo development of alloprimed CXCR3+CCR4+CD8+ T cells.

  • CXCR3+CCR4+CD8+ T cells are a multipotent, highly cytotoxic CD8+ T cell subset.

Visual Abstract

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

Abstract

Hepatocyte transplant represents a treatment for metabolic disorders but is limited by immunogenicity. Our prior work identified the critical role of CD8+ T cells, with or without CD4+ T cell help, in mediating hepatocyte rejection. In this study, we evaluated the influence of invariant NKT (iNKT) cells, uniquely abundant in the liver, upon CD8-mediated immune responses in the presence and absence of CD4+ T cells. To investigate this, C57BL/6 (wild-type) and iNKT-deficient Jα18 knockout mice (cohorts CD4 depleted) were transplanted with allogeneic hepatocytes. Recipients were evaluated for alloprimed CD8+ T cell subset composition, allocytotoxicity, and hepatocyte rejection. We found that CD8-mediated allocytotoxicity was significantly decreased in iNKT-deficient recipients and was restored by adoptive transfer of iNKT cells. In the absence of both iNKT cells and CD4+ T cells, CD8-mediated allocytotoxicity and hepatocyte rejection was abrogated. iNKT cells enhance the proportion of a novel subset of multipotent, alloprimed CXCR3+CCR4+CD8+ cytolytic T cells that develop after hepatocyte transplant and are abundant in the liver. Alloprimed CXCR3+CCR4+CD8+ T cells express cytotoxic effector molecules (perforin/granzyme and Fas ligand) and are distinguished from alloprimed CXCR3+CCR4−CD8+ T cells by a higher proportion of cells expressing TNF-α and IFN-γ. Furthermore, alloprimed CXCR3+CCR4+CD8+ T cells mediate higher allocytotoxicity and more rapid allograft rejection. Our data demonstrate the important role of iNKT cells in promoting the development of highly cytotoxic, multipotent CXCR3+CCR4+CD8+ T cells that mediate rapid rejection of allogeneic hepatocytes engrafted in the liver. Targeting iNKT cells may be an efficacious therapy to prevent rejection of intrahepatic cellular transplants.

This article is featured in Top Reads, p.

Footnotes

  • This work was supported by National Institute of Allergy and Infectious Diseases, National Institutes of Health R01 Grant AI083456 (to G.L.B.) and T32AI106704 (to J.H.), The Ohio State University (OSU) College of Medicine Roessler Research scholarship (to B.A.R.), CA016058, UL1TR002733, the OSU Division of Transplant Surgery, and the OSU College of Medicine. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article

    AT
    adoptive transfer
    DC
    dendritic cell
    DN
    double-negative
    FasL
    Fas ligand
    α-GalCer
    α-galactosylceramide
    hA1AT
    human α-1 antitrypsin
    iNKT
    invariant NKT
    KO
    knockout
    LMNC
    liver mononuclear cell
    MST
    median survival time
    Treg
    regulatory T cell
    WT
    wild-type

  • Received April 8, 2021.
  • Accepted October 13, 2021.
  • Copyright © 2021 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: 207 (12)
The Journal of Immunology
Vol. 207, Issue 12
15 Dec 2021
  • 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.
Invariant NKT Cells Promote the Development of Highly Cytotoxic Multipotent CXCR3+CCR4+CD8+ T Cells That Mediate Rapid Hepatocyte Allograft Rejection
(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
Invariant NKT Cells Promote the Development of Highly Cytotoxic Multipotent CXCR3+CCR4+CD8+ T Cells That Mediate Rapid Hepatocyte Allograft Rejection
Jason M. Zimmerer, Bryce A. Ringwald, Sachi R. Chaudhari, Jing Han, Chelsea M. Peterson, Robert T. Warren, Madison M. Hart, Mahmoud Abdel-Rasoul, Ginny L. Bumgardner
The Journal of Immunology December 15, 2021, 207 (12) 3107-3121; DOI: 10.4049/jimmunol.2100334

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Invariant NKT Cells Promote the Development of Highly Cytotoxic Multipotent CXCR3+CCR4+CD8+ T Cells That Mediate Rapid Hepatocyte Allograft Rejection
Jason M. Zimmerer, Bryce A. Ringwald, Sachi R. Chaudhari, Jing Han, Chelsea M. Peterson, Robert T. Warren, Madison M. Hart, Mahmoud Abdel-Rasoul, Ginny L. Bumgardner
The Journal of Immunology December 15, 2021, 207 (12) 3107-3121; DOI: 10.4049/jimmunol.2100334
del.icio.us logo Digg logo Reddit logo Twitter 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
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Innate and Adaptive Immunity to Transfused Allogeneic RBCs in Mice Requires MyD88
  • Functional Competence of NK Cells via the KIR/MHC Class I Interaction Correlates with DNAM-1 Expression
Show more TRANSPLANTATION

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
  • FAR 889
  • Privacy Policy
  • Disclaimer

Journal Services

  • Email Alerts
  • RSS Feeds
  • ImmunoCasts
  • Twitter

Copyright © 2022 by The American Association of Immunologists, Inc.

Print ISSN 0022-1767        Online ISSN 1550-6606