Lineage extrinsic and intrinsic control of immunoregulatory cell numbers by SHIP

Authors

  • Michelle M. Collazo,

    1. Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL, USA
    2. Moffitt Cancer Center, Tampa, FL, USA
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  • Kim H. T. Paraiso,

    1. Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL, USA
    2. Moffitt Cancer Center, Tampa, FL, USA
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  • Mi-Young Park,

    1. Department of Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY, USA
    2. Department of Pediatrics, SUNY Upstate Medical University, Syracuse, NY, USA
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  • Amy L. Hazen,

    1. Medical School, Health Science Center at Houston, The University of Texas, Houston, TX, USA
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  • William G. Kerr

    Corresponding author
    1. Department of Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY, USA
    2. Department of Pediatrics, SUNY Upstate Medical University, Syracuse, NY, USA
    3. Department of Chemistry, Syracuse University, Syracuse, NY, USA
    • Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL, USA
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  • See accompanying Commentary by Corey et al.

Full correspondence: Dr. William G. Kerr, SUNY Upstate Medical University, 750 E. Adams Street, 2204 Weiskotten Hall, Syracuse, NY 13210, USA

Fax: +1-315-464-4417

e-mail: kerrw@upstate.edu

See accompanying article: http://dx.doi.org/10.1002/eji.2012201242706

Abstract

We previously showed that germline or induced SHIP deficiency expands immuno-regulatory cell numbers in T lymphoid and myeloid lineages. We postulated these increases could be interrelated. Here, we show that myeloid-specific ablation of SHIP leads to the expansion of both myeloid-derived suppressor cell (MDSC) and regulatory T (Treg) cell numbers, indicating SHIP-dependent control of Treg-cell numbers by a myeloid cell type. Conversely, T-lineage specific ablation of SHIP leads to expansion of Treg-cell numbers, but not expansion of the MDSC compartment, indicating SHIP also has a lineage intrinsic role in limiting Treg-cell numbers. However, the SHIP-deficient myeloid cell that promotes MDSC and Treg-cell expansion is not an MDSC as they lack SHIP protein expression. Thus, regulation of MDSC numbers in vivo must be controlled in a cell-extrinsic fashion by another myeloid cell type. We had previously shown that G-CSF levels are profoundly increased in SHIP−/− mice, suggesting this myelopoietic growth factor could promote MDSC expansion in a cell-extrinsic fashion. Consistent with this hypothesis, we find that G-CSF is required for expansion of the MDSC splenic compartment in mice rendered SHIP-deficient as adults. Thus, SHIP controls MDSC numbers, in part, by limiting production of the myelopoietic growth factor G-CSF.

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