Critical roles of mTOR Complex 1 and 2 for T follicular helper cell differentiation and germinal center responses

  1. Jialong Yang
  2. Xingguang Lin
  3. Yun Pan
  4. Jinli Wang
  5. Pengcheng Chen
  6. Hongxiang Huang
  7. Hai-Hui Xue
  8. Jimin Gao
  9. Xiao-Ping Zhong  Is a corresponding author
  1. Duke University Medical Center, United States
  2. Wenzhou Medical University, China
  3. University of Iowa, United States

Abstract

T Follicular helper T (Tfh) cells play critical roles for germinal center responses and effective humoral immunity. We report here that mTOR in CD4 T cells is essential for Tfh differentiation. In Mtorf/f-Cd4Cre mice, both constitutive and inducible Tfh differentiation is severely impaired, leading to defective germinal center B cell formation and antibody production. Moreover, both mTORC1 and mTORC2 contribute to Tfh and GC B cell development but may do so via distinct mechanisms. mTORC1 mainly promotes CD4 T cell proliferation to reach the cell divisions necessary for Tfh differentiation, while Rictor/mTORC2 regulates Tfh differentiation by promoting Akt activation and TCF1 expression without grossly influencing T cell proliferation. Together, our results reveal crucial but distinct roles for mTORC1 and mTORC2 in CD4 T cells during Tfh differentiation and germinal center responses.

Article and author information

Author details

  1. Jialong Yang

    Department of Pediatrics, Duke University Medical Center, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Xingguang Lin

    Department of Pediatrics, Duke University Medical Center, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Yun Pan

    Department of Pediatrics, Duke University Medical Center, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jinli Wang

    School of Laboratory Medicine, Wenzhou Medical University, Wenzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Pengcheng Chen

    School of Laboratory Medicine, Wenzhou Medical University, Wenzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Hongxiang Huang

    Department of Pediatrics, Duke University Medical Center, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Hai-Hui Xue

    Department of Microbiology, University of Iowa, Iowa, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Jimin Gao

    School of Laboratory Medicine, Wenzhou Medical University, Wenzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Xiao-Ping Zhong

    Department of Pediatrics, Duke University Medical Center, Durham, United States
    For correspondence
    xiaoping.zhong@duke.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4619-8783

Funding

National Institutes of Health (R01AI079088)

  • Xiao-Ping Zhong

National Institutes of Health (R01AI101206)

  • Xiao-Ping Zhong

National Institutes of Health (R01AI112579)

  • Hai-Hui Xue

National Institutes of Health (R01AI115149)

  • Hai-Hui Xue

National Institutes of Health (R01AI119160)

  • Hai-Hui Xue

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols A051-16-03 and A095-13-04) of Duke University.

Copyright

© 2016, Yang 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

  • 2,718
    views
  • 779
    downloads
  • 88
    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. Jialong Yang
  2. Xingguang Lin
  3. Yun Pan
  4. Jinli Wang
  5. Pengcheng Chen
  6. Hongxiang Huang
  7. Hai-Hui Xue
  8. Jimin Gao
  9. Xiao-Ping Zhong
(2016)
Critical roles of mTOR Complex 1 and 2 for T follicular helper cell differentiation and germinal center responses
eLife 5:e17936.
https://doi.org/10.7554/eLife.17936

Share this article

https://doi.org/10.7554/eLife.17936

Further reading

    1. Immunology and Inflammation
    Fani Roumelioti, Christos Tzaferis ... George Kollias
    Research Article

    miRNAs constitute fine-tuners of gene expression and are implicated in a variety of diseases spanning from inflammation to cancer. miRNA expression is deregulated in rheumatoid arthritis (RA); however, their specific role in key arthritogenic cells such as the synovial fibroblast (SF) remains elusive. Previous studies have shown that Mir221/222 expression is upregulated in RA SFs. Here, we demonstrate that TNF and IL-1β but not IFN-γ activated Mir221/222 gene expression in murine SFs. SF-specific overexpression of Mir221/222 in huTNFtg mice led to further expansion of SFs and disease exacerbation, while its total ablation led to reduced SF expansion and attenuated disease. Mir221/222 overexpression altered the SF transcriptional profile igniting pathways involved in cell cycle and ECM (extracellular matrix) regulation. Validation of targets of Mir221/222 revealed cell cycle inhibitors Cdkn1b and Cdkn1c, as well as the epigenetic regulator Smarca1. Single-cell ATAC-seq data analysis revealed increased Mir221/222 gene activity in pathogenic SF subclusters and transcriptional regulation by Rela, Relb, Junb, Bach1, and Nfe2l2. Our results establish an SF-specific pathogenic role of Mir221/222 in arthritis and suggest that its therapeutic targeting in specific subpopulations could lead to novel fibroblast-targeted therapies.

    1. Immunology and Inflammation
    Youxi Liu, Meimei Yin ... Ling-juan Zhang
    Research Article

    Allergic contact dermatitis (ACD), a prevalent inflammatory skin disease, is elicited upon repeated skin contact with protein-reactive chemicals through a complex and poorly characterized cellular network between immune cells and skin resident cells. Here, single-cell transcriptomic analysis of the murine hapten-elicited model of ACD reveals that upon elicitation of ACD, infiltrated CD4+ or CD8+ lymphocytes were primarily the IFNγ-producing type 1 central memory phenotype. In contrast, type 2 cytokines (IL4 and IL13) were dominantly expressed by basophils, IL17A was primarily expressed by δγ T cells, and IL1β was identified as the primary cytokine expressed by activated neutrophils/monocytes and macrophages. Furthermore, analysis of skin resident cells identified a sub-cluster of dermal fibroblasts with preadipocyte signature as a prominent target for IFNγ+ lymphocytes and dermal source for key T cell chemokines CXCL9/10. IFNγ treatment shifted dermal fibroblasts from collagen-producing to CXCL9/10-producing, which promoted T cell polarization toward the type-1 phenotype through a CXCR3-dependent mechanism. Furthermore, targeted deletion of Ifngr1 in dermal fibroblasts in mice reduced Cxcl9/10 expression, dermal infiltration of CD8+ T cell, and alleviated ACD inflammation in mice. Finally, we showed that IFNγ+ CD8+ T cells and CXCL10-producing dermal fibroblasts co-enriched in the dermis of human ACD skin. Together, our results define the cell type-specific immune responses in ACD, and recognize an indispensable role of dermal fibroblasts in shaping the development of type-1 skin inflammation through the IFNGR-CXCR3 signaling circuit during ACD pathogenesis.