1. Cell Biology
  2. Immunology and Inflammation
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Signal transducer and activator of transcription 5 (STAT5) paralog dose governs T cell effector and regulatory functions

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Cite this article as: eLife 2016;5:e08384 doi: 10.7554/eLife.08384

Abstract

The transcription factor STAT5 is fundamental to the mammalian immune system. However, the relationship between its two paralogs, STAT5A and STAT5B, and the extent to which they are functionally distinct, remains uncertain. Using mouse models of paralog deficiency, we demonstrate that they are not equivalent for CD4+ 'helper' T cells, the principal orchestrators of adaptive immunity. Instead, we find that STAT5B is dominant in both effector and regulatory (Treg) responses and, therefore, uniquely necessary for immunological tolerance. Comparative analysis of genomic distribution and transcriptomic output reveals that STAT5B has greater transcriptional output but, surprisingly, our data point towards asymmetric expression (i.e. paralog dose), rather than distinct functional properties, as the key distinguishing feature. Thus, we propose a quantitative model of STAT5 paralog activity whereby relative abundance imposes functional specificity (or dominance) in the face of widespread structural homology.

Article and author information

Author details

  1. Alejandro Villarino

    Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, United States
    For correspondence
    alejandro.villarino@nih.gov
    Competing interests
    No competing interests declared.
  2. Arian Laurence

    Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  3. Gertraud W Robinson

    Laboratory of Genetics and Physiology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  4. Michael Bonelli

    Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  5. Barbara Dema

    Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  6. Behdad Afzali

    Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  7. Han-Yu Shih

    Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  8. Hong-Wei Sun

    Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  9. Stephen R Brooks

    Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  10. Lothar Hennighausen

    Laboratory of Genetics and Physiology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  11. Yuka Kanno

    Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  12. John J O'Shea

    Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, United States
    Competing interests
    John J O'Shea, J.J.O'S. and the NIH hold patents related to therapeutic targeting of Jak kinases and have a Collaborative Research Agreement and Development Award with Pfizer Inc..

Ethics

Animal experimentation: Animals were handled in accordance with NIH guidelines and all experiments approved by the NIAMS Animal Care and Use Committee (Animal Study Number: A013-10-07).

Reviewing Editor

  1. Christopher K Glass, University of California, San Diego, United States

Publication history

  1. Received: April 28, 2015
  2. Accepted: March 18, 2016
  3. Accepted Manuscript published: March 19, 2016 (version 1)
  4. Version of Record published: May 4, 2016 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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