Somatic hypermutation of T cell receptor α chain contributes to selection in nurse shark thymus

  1. Jeannine A Ott
  2. Caitlin D Castro
  3. Thaddeus C Deiss
  4. Yuko Ohta
  5. Martin F Flajnik
  6. Michael F Criscitiello  Is a corresponding author
  1. Texas A&M University, United States
  2. University of Maryland, United States

Abstract

Since the discovery of the T cell receptor (TcR), immunologists have assigned somatic hypermutation (SHM) as a mechanism employed solely by B cells to diversify their antigen receptors. Remarkably, we found SHM acting in the thymus on α chain locus of shark TcR. SHM in developing shark T cells likely is catalyzed by activation-induced cytidine deaminase (AID) and results in both point and tandem mutations that accumulate non-conservative amino acid replacements within complementarity-determining regions (CDRs). Mutation frequency at TcRα was as high as that seen at B cell receptor loci (BcR) in sharks and mammals, and the mechanism of SHM shares unique characteristics first detected at shark BcR loci. Additionally, fluorescence in situ hybridization showed the strongest AID expression in thymic corticomedullary junction and medulla. We suggest that TcRα utilizes SHM to broaden diversification of the primary αβ T cell repertoire in sharks, the first reported use in vertebrates.

Data availability

T cell receptor sequences have been deposited in Genbank of NCBI.Alpha KY189332-KY189354 and KY366469-KY355487;Beta KY351708-KY366487;Gamma KY351639-KY351707;Delta KY346705-KY346816

Article and author information

Author details

  1. Jeannine A Ott

    Comparative Immunogenetics Laboratory, Department of Veterinary Pathobiology College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3537-8631
  2. Caitlin D Castro

    Department of Microbiology and Immunology, University of Maryland, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Thaddeus C Deiss

    Comparative Immunogenetics Laboratory, Department of Veterinary Pathobiology College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Yuko Ohta

    Department of Microbiology and Immunology, University of Maryland, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Martin F Flajnik

    Department of Microbiology and Immunology, University of Maryland, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Michael F Criscitiello

    Comparative Immunogenetics Laboratory, Department of Veterinary Pathobiology College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, United States
    For correspondence
    MCRISCITIELLO@CVM.TAMU.EDU
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4262-7832

Funding

National Science Foundation (IOS 1257829)

  • Michael F Criscitiello

National Institute of Allergy and Infectious Diseases (R01OD0549)

  • Martin F Flajnik

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. David G Schatz, Yale University School of Medicine, United States

Ethics

Animal experimentation: These studies were carried out in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The protocol was approved by the Animal Care and Use Committees at Texas A&M University and University of Maryland School of Medicine. Experiments in the Criscitiello lab were performed under Texas A&M University Institutional Biosafety Committee permit IBC 2014-293 and Animal Use Protocol 2015-0374.

Version history

  1. Received: May 9, 2017
  2. Accepted: April 16, 2018
  3. Accepted Manuscript published: April 17, 2018 (version 1)
  4. Version of Record published: May 2, 2018 (version 2)
  5. Version of Record updated: May 2, 2018 (version 3)

Copyright

© 2018, Ott et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 2,654
    Page views
  • 313
    Downloads
  • 31
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Jeannine A Ott
  2. Caitlin D Castro
  3. Thaddeus C Deiss
  4. Yuko Ohta
  5. Martin F Flajnik
  6. Michael F Criscitiello
(2018)
Somatic hypermutation of T cell receptor α chain contributes to selection in nurse shark thymus
eLife 7:e28477.
https://doi.org/10.7554/eLife.28477

Share this article

https://doi.org/10.7554/eLife.28477

Further reading

    1. Developmental Biology
    2. Immunology and Inflammation
    Amir Hossein Kayvanjoo, Iva Splichalova ... Elvira Mass
    Research Article

    During embryogenesis, the fetal liver becomes the main hematopoietic organ, where stem and progenitor cells as well as immature and mature immune cells form an intricate cellular network. Hematopoietic stem cells (HSCs) reside in a specialized niche, which is essential for their proliferation and differentiation. However, the cellular and molecular determinants contributing to this fetal HSC niche remain largely unknown. Macrophages are the first differentiated hematopoietic cells found in the developing liver, where they are important for fetal erythropoiesis by promoting erythrocyte maturation and phagocytosing expelled nuclei. Yet, whether macrophages play a role in fetal hematopoiesis beyond serving as a niche for maturing erythroblasts remains elusive. Here, we investigate the heterogeneity of macrophage populations in the murine fetal liver to define their specific roles during hematopoiesis. Using a single-cell omics approach combined with spatial proteomics and genetic fate-mapping models, we found that fetal liver macrophages cluster into distinct yolk sac-derived subpopulations and that long-term HSCs are interacting preferentially with one of the macrophage subpopulations. Fetal livers lacking macrophages show a delay in erythropoiesis and have an increased number of granulocytes, which can be attributed to transcriptional reprogramming and altered differentiation potential of long-term HSCs. Together, our data provide a detailed map of fetal liver macrophage subpopulations and implicate macrophages as part of the fetal HSC niche.

    1. Immunology and Inflammation
    2. Microbiology and Infectious Disease
    Yuting Zhang, Min Zhang ... Guojiang Chen
    Research Article

    Marburg virus (MARV) is one of the filovirus species that cause deadly hemorrhagic fever in humans, with mortality rates up to 90%. Neutralizing antibodies represent ideal candidates to prevent or treat virus disease. However, no antibody has been approved for MARV treatment to date. In this study, we identified a novel human antibody named AF-03 that targeted MARV glycoprotein (GP). AF-03 possessed a high binding affinity to MARV GP and showed neutralizing and protective activities against the pseudotyped MARV in vitro and in vivo. Epitope identification, including molecular docking and experiment-based analysis of mutated species, revealed that AF-03 recognized the Niemann-Pick C1 (NPC1) binding domain within GP1. Interestingly, we found the neutralizing activity of AF-03 to pseudotyped Ebola viruses (EBOV, SUDV, and BDBV) harboring cleaved GP instead of full-length GP. Furthermore, NPC2-fused AF-03 exhibited neutralizing activity to several filovirus species and EBOV mutants via binding to CI-MPR. In conclusion, this work demonstrates that AF-03 represents a promising therapeutic cargo for filovirus-caused disease.