Cell-intrinsic and -extrinsic control of Treg-cell homeostasis and function revealed by induced CD28 deletion

Authors

  • Tea Gogishvili,

    1. Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany
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  • Fred Lühder,

    1. Department of Neuroimmunology, Institute for Multiple Sclerosis Research and The Hertie Foundation, University Medical Center Göttingen, Göttingen, Germany
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  • Sandra Goebbels,

    1. Max Planck Institute of Experimental Medicine, Neurogenetics, Göttingen, Germany
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  • Sandra Beer-Hammer,

    1. Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, University of Tübingen, Tübingen, Germany
    2. Interfaculty Center of Pharmacogenomics and Drug Research, University of Tübingen, Tübingen, Germany
    3. Institute of Medical Microbiology and Hospital Hygiene, Clinical Centre of Heinrich Heine University, Düsseldorf, Germany
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  • Klaus Pfeffer,

    1. Institute of Medical Microbiology and Hospital Hygiene, Clinical Centre of Heinrich Heine University, Düsseldorf, Germany
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  • Thomas Hünig

    Corresponding author
    • Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany
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Full Correspondence: Dr. Thomas Hünig, Institute for Virology and Immunobiology, University of Würzburg, Versbacher str. 7, 97078 Würzburg, Germany

Fax: +49-931-49-243

e-mail: huenig@vim.uni-wuerzburg.de

See accompanying Commentary by Sansom and Walker

Abstract

While the requirement for CD28 and its ligands for the generation and function of “natural” (n)Treg cells is well established, it has not been possible yet to investigate cell-intrinsic effects after interrupted CD28 expression. Here, we demonstrate a selective loss of Treg cells after disruption of the CD28 gene. The decline in Treg-cell number was accompanied by reduced homeostatic proliferation, probably due to lack of costimulation during self-antigen recognition, and by impaired Treg-cell function including downregulation of CTLA-4. The decline in Treg-cell number was unaffected by thymectomy or by the presence of CD28 expressing T cells within the same animal, indicating that impairment of peripheral homeostasis and function of nTreg cells by CD28 deletion is cell-intrinsic. In contrast, downregulation of CD25, the α chain of the IL-2R, did not occur in the presence of WT T cells, indicating that its expression does not depend on CD28 signals in cis.

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