Conditional deletion of SLP-76 in mature T cells abrogates peripheral immune responses

Authors

  • Gregory F. Wu,

    1. Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
    Current affiliation:
    1. Department of Neurology, Washington University in St. Louis, 660 S. Euclid Ave, Box 8111, St. Louis, MO 633110, USA
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    • These authors contributed equally to the work.

  • Evann Corbo,

    1. Renal Electrolyte and Hypertension Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
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    • These authors contributed equally to the work.

  • Michelle Schmidt,

    1. Renal Electrolyte and Hypertension Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
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  • Jennifer E. Smith-Garvin,

    1. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
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  • Matthew J. Riese,

    1. Hematology-Oncology Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
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  • Martha S. Jordan,

    1. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
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  • Terri M. Laufer,

    1. Rheumatology Division, Department of Medicine, University of Pennsylvania School of Medicine and Philadelphia Veterans Affairs Medical Center, Philadelphia, PA, USA
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  • Eric J. Brown,

    1. Abramson Family Cancer Research Institute and the Department of Cancer Biology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
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  • Jonathan S. Maltzman

    Corresponding author
    1. Renal Electrolyte and Hypertension Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
    • Department of Medicine, University of Pennsylvania, 754 BRB II/III, 421 Curie Blvd, Philadelphia, PA 19104, USA Fax: +1-215-573-7599

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Abstract

The adaptor protein Src homology 2 domain-containing leukocyte-specific protein of 76 kDa (SLP-76) is central to the organization of intracellular signaling downstream of the T-cell receptor (TCR). Evaluation of its role in mature, primary T cells has been hampered by developmental defects that occur in the absence of WT SLP-76 protein in thymocytes. Here, we show that following tamoxifen-regulated conditional deletion of SLP-76, mature, antigen-inexperienced T cells maintain normal TCR surface expression but fail to transduce TCR-generated signals. Conditionally deficient T cells fail to proliferate in response to antigenic stimulation or a lymphopenic environment. Mice with induced deletion of SLP-76 are resistant to induction of the CD4+ T-cell-mediated autoimmune disease experimental autoimmune encephalomyelitis. Altogether, our findings demonstrate the critical role of SLP-76-mediated signaling in initiating T-cell-directed immune responses both in vitro and in vivo and highlight the ability to analyze signaling processes in mature T cells in the absence of developmental defects.

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