Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Naïve CD8 T cell IFNγ responses to a vacuolar antigen are regulated by an inflammasome-independent NLRP3 pathway and Toxoplasma gondii ROP5

Angel K. Kongsomboonvech, Felipe Rodriguez, Anh L. Diep, View ORCID ProfileBrandon M. Justice, View ORCID ProfileBrayan E. Castallanos, Ana Camejo, View ORCID ProfileDebanjan Mukhopadhyay, View ORCID ProfileGregory A. Taylor, View ORCID ProfileMasahiro Yamamoto, View ORCID ProfileJeroen P.J. Saeij, Michael L. Reese, View ORCID ProfileKirk D.C. Jensen
doi: https://doi.org/10.1101/2020.01.20.912568
Angel K. Kongsomboonvech
1Department of Molecular and Cell Biology, University of California, Merced, Merced, California 95343, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Felipe Rodriguez
1Department of Molecular and Cell Biology, University of California, Merced, Merced, California 95343, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Anh L. Diep
1Department of Molecular and Cell Biology, University of California, Merced, Merced, California 95343, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Brandon M. Justice
1Department of Molecular and Cell Biology, University of California, Merced, Merced, California 95343, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Brandon M. Justice
Brayan E. Castallanos
1Department of Molecular and Cell Biology, University of California, Merced, Merced, California 95343, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Brayan E. Castallanos
Ana Camejo
2Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Debanjan Mukhopadhyay
3Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California, Davis, Davis, California 95616, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Debanjan Mukhopadhyay
Gregory A. Taylor
4Departments of Medicine; Molecular Genetics and Microbiology; and Immunology; and Center for the Study of Aging and Human Development, Duke University Medical Center, Durham, NC 27710; and Geriatric Research, Education, and Clinical Center, Durham VA Health Care System, Durham, NC 27705, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Gregory A. Taylor
Masahiro Yamamoto
5Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Masahiro Yamamoto
Jeroen P.J. Saeij
3Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California, Davis, Davis, California 95616, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Jeroen P.J. Saeij
Michael L. Reese
6Department of Pharmacology, University of Texas, Southwestern Medical Center, Dallas, Texas 75390, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kirk D.C. Jensen
1Department of Molecular and Cell Biology, University of California, Merced, Merced, California 95343, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Kirk D.C. Jensen
  • For correspondence: kjensen5@ucmerced.edu
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Preview PDF
Loading

ABSTRACT

Host resistance to Toxoplasma gondii relies on CD8 T cell IFNγ responses, which if modulated by the host or parasite could influence chronic infection and parasite transmission between hosts. Since host-parasite interactions that govern this response are not fully elucidated, we investigated requirements for eliciting naïve CD8 T cell IFNγ responses to a vacuolar resident antigen of T. gondii, TGD057. Naïve TGD057 antigen-specific CD8 T cells (T57) were isolated from transnuclear mice and responded to parasite-infected bone marrow-derived macrophages (BMDMs) in an antigen-dependent manner, first by producing IL-2 and then IFNγ. T57 IFNγ responses to TGD057 were independent of the parasite’s protein export machinery ASP5 and MYR1. Instead, host immunity pathways downstream of the regulatory Immunity-Related GTPases (IRG), including partial dependence on Guanylate-Binding Proteins, are required. Multiple T. gondii ROP5 isoforms and allele types, including ‘avirulent’ ROP5A from clade A and D parasite strains, were able to suppress CD8 T cell IFNγ responses to parasite-infected BMDMs. Phenotypic variance between clades B, C, D, F, and A strains suggest T57 IFNγ differentiation occurs independently of parasite virulence or any known IRG-ROP5 interaction. Consistent with this, removal of ROP5 is not enough to elicit maximal CD8 T cell IFNγ production to parasite-infected cells. Instead, macrophage expression of the pathogen sensors, NLRP3 and to a large extent NLRP1, were absolute requirements. Other members of the conventional inflammasome cascade are only partially required, as revealed by decreased but not abrogated T57 IFNγ responses to parasite-infected ASC, caspase-1/11, and gasdermin D deficient cells. Moreover, IFNγ production was only partially reduced in the absence of IL-12, IL-18 or IL-1R signaling. In summary, T. gondii effectors and host machinery that modulate parasitophorous vacuolar membranes, as well as NLR-dependent but inflammasome-independent pathways, determine the full commitment of CD8 T cells IFNγ responses to a vacuolar antigen.

AUTHOR SUMMARY Parasites are excellent “students” of our immune system as they can deflect, antagonize and confuse the immune response making it difficult to vaccinate against these pathogens. In this report, we analyzed how a widespread parasite of mammals, Toxoplasma gondii, manipulates an immune cell needed for immunity to many intracellular pathogens, the CD8 T cell. Host pathways that govern CD8 T cell production of the immune protective cytokine, IFNγ, were also explored. We hypothesized the secreted Toxoplasma virulence factor, ROP5, work to inhibit the MHC 1 antigen presentation pathway therefore making it difficult for CD8 T cells to see T. gondii antigens sequestered inside a parasitophorous vacuole. However, manipulation through T. gondii ROP5 does not fully explain how CD8 T cells commit to making IFNγ in response to infection. Importantly, CD8 T cell IFNγ responses to T. gondii require the pathogen sensor NLRP3 to be expressed in the infected cell. Other proteins associated with NLRP3 activation, including members of the conventional inflammasome activation cascade pathway, are only partially involved. Our results identify a novel pathway by which NLRP3 regulates T cell function and underscore the need for inflammasome-activating adjuvants in vaccines aimed at inducing CD8 T cell IFNγ responses to parasites.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
Back to top
PreviousNext
Posted January 20, 2020.
Download PDF
Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Naïve CD8 T cell IFNγ responses to a vacuolar antigen are regulated by an inflammasome-independent NLRP3 pathway and Toxoplasma gondii ROP5
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Naïve CD8 T cell IFNγ responses to a vacuolar antigen are regulated by an inflammasome-independent NLRP3 pathway and Toxoplasma gondii ROP5
Angel K. Kongsomboonvech, Felipe Rodriguez, Anh L. Diep, Brandon M. Justice, Brayan E. Castallanos, Ana Camejo, Debanjan Mukhopadhyay, Gregory A. Taylor, Masahiro Yamamoto, Jeroen P.J. Saeij, Michael L. Reese, Kirk D.C. Jensen
bioRxiv 2020.01.20.912568; doi: https://doi.org/10.1101/2020.01.20.912568
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
Naïve CD8 T cell IFNγ responses to a vacuolar antigen are regulated by an inflammasome-independent NLRP3 pathway and Toxoplasma gondii ROP5
Angel K. Kongsomboonvech, Felipe Rodriguez, Anh L. Diep, Brandon M. Justice, Brayan E. Castallanos, Ana Camejo, Debanjan Mukhopadhyay, Gregory A. Taylor, Masahiro Yamamoto, Jeroen P.J. Saeij, Michael L. Reese, Kirk D.C. Jensen
bioRxiv 2020.01.20.912568; doi: https://doi.org/10.1101/2020.01.20.912568

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Immunology
Subject Areas
All Articles
  • Animal Behavior and Cognition (4113)
  • Biochemistry (8815)
  • Bioengineering (6518)
  • Bioinformatics (23462)
  • Biophysics (11789)
  • Cancer Biology (9208)
  • Cell Biology (13322)
  • Clinical Trials (138)
  • Developmental Biology (7436)
  • Ecology (11409)
  • Epidemiology (2066)
  • Evolutionary Biology (15150)
  • Genetics (10436)
  • Genomics (14043)
  • Immunology (9171)
  • Microbiology (22154)
  • Molecular Biology (8812)
  • Neuroscience (47568)
  • Paleontology (350)
  • Pathology (1428)
  • Pharmacology and Toxicology (2491)
  • Physiology (3730)
  • Plant Biology (8080)
  • Scientific Communication and Education (1437)
  • Synthetic Biology (2221)
  • Systems Biology (6037)
  • Zoology (1253)