Mycolic acid-specific T Cells protect against Mycobacterium Tuberculosis infection in a humanized transgenic mouse model

Abstract

Group 1 CD1 molecules, CD1a, CD1b and CD1c, present lipid antigens from Mycobacterium tuberculosis (Mtb) to T cells. Mtb lipid-specific group 1 CD1-restricted T cells have been detected in Mtb-infected individuals. However, their role in protective immunity against Mtb remains unclear due to the absence of group 1 CD1 expression in mice. To overcome the challenge, we generated mice that expressed human group 1 CD1 molecules (hCD1Tg) and a CD1b-restricted, mycolic-acid specific TCR (DN1Tg). Using DN1Tg/hCD1Tg mice, we found that activation of DN1 T cells was initiated in the mediastinal lymph nodes and showed faster kinetics compared to Mtb Ag85B-specific CD4+ T cells after aerosol infection with Mtb. Additionally, activated DN1 T cells exhibited polyfunctional characteristics, accumulated in lung granulomas, and protected against Mtb infection. Therefore, our findings highlight the vaccination potential of targeting group 1 CD1-restricted lipid-specific T cells against Mtb infection.

Article and author information

Author details

  1. Jie Zhao

    Department of Microbiology and Immunology, Northwestern University, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Sarah Siddiqui

    Department of Microbiology and Immunology, Northwestern University, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Shaobin Shang

    Department of Microbiology and Immunology, Northwestern University, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Yao Bian

    Department of Microbiology and Immunology, Northwestern University, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Sreya Bagchi

    Department of Microbiology and Immunology, Northwestern University, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Ying He

    Department of Microbiology and Immunology, Northwestern University, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Chyung-Ru Wang

    Department of Microbiology and Immunology, Northwestern University, Chicago, United States
    For correspondence
    chyung-ru-wang@northwestern.edu
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: This study was 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 Committee of the Northwestern University (Protocol number: 2012-1736).

Copyright

© 2015, Zhao 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

  • 3,293
    views
  • 477
    downloads
  • 45
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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. Jie Zhao
  2. Sarah Siddiqui
  3. Shaobin Shang
  4. Yao Bian
  5. Sreya Bagchi
  6. Ying He
  7. Chyung-Ru Wang
(2015)
Mycolic acid-specific T Cells protect against Mycobacterium Tuberculosis infection in a humanized transgenic mouse model
eLife 4:e08525.
https://doi.org/10.7554/eLife.08525

Share this article

https://doi.org/10.7554/eLife.08525

Further reading

    1. Immunology and Inflammation
    Denise M Monack
    Insight

    Macrophages control intracellular pathogens like Salmonella by using two caspase enzymes at different times during infection.

    1. Immunology and Inflammation
    2. Medicine
    Haiyi Fei, Xiaowen Lu ... Lingling Jiang
    Research Article

    Preeclampsia (PE), a major cause of maternal and perinatal mortality with highly heterogeneous causes and symptoms, is usually complicated by gestational diabetes mellitus (GDM). However, a comprehensive understanding of the immune microenvironment in the placenta of PE and the differences between PE and GDM is still lacking. In this study, cytometry by time of flight indicated that the frequencies of memory-like Th17 cells (CD45RACCR7+IL-17A+CD4+), memory-like CD8+ T cells (CD38+CXCR3CCR7+HeliosCD127CD8+) and pro-inflam Macs (CD206CD163CD38midCD107alowCD86midHLA-DRmidCD14+) were increased, while the frequencies of anti-inflam Macs (CD206+CD163CD86midCD33+HLA-DR+CD14+) and granulocyte myeloid-derived suppressor cells (gMDSCs, CD11b+CD15hiHLA-DRlow) were decreased in the placenta of PE compared with that of normal pregnancy (NP), but not in that of GDM or GDM&PE. The pro-inflam Macs were positively correlated with memory-like Th17 cells and memory-like CD8+ T cells but negatively correlated with gMDSCs. Single-cell RNA sequencing revealed that transferring the F4/80+CD206 pro-inflam Macs with a Folr2+Ccl7+Ccl8+C1qa+C1qb+C1qc+ phenotype from the uterus of PE mice to normal pregnant mice induced the production of memory-like IL-17a+Rora+Il1r1+TNF+Cxcr6+S100a4+CD44+ Th17 cells via IGF1–IGF1R, which contributed to the development and recurrence of PE. Pro-inflam Macs also induced the production of memory-like CD8+ T cells but inhibited the production of Ly6g+S100a8+S100a9+Retnlg+Wfdc21+ gMDSCs at the maternal–fetal interface, leading to PE-like symptoms in mice. In conclusion, this study revealed the PE-specific immune cell network, which was regulated by pro-inflam Macs, providing new ideas about the pathogenesis of PE.