Lineage extrinsic and intrinsic control of immunoregulatory cell numbers by SHIP

Eur J Immunol. 2012 Jul;42(7):1785-95. doi: 10.1002/eji.201142092.


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.

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Lineage
  • Cell Survival / immunology
  • Flow Cytometry
  • Granulocyte Colony-Stimulating Factor / immunology*
  • Inositol Polyphosphate 5-Phosphatases
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Myeloid Cells / cytology
  • Myeloid Cells / immunology*
  • Phosphoric Monoester Hydrolases / genetics
  • Phosphoric Monoester Hydrolases / immunology*
  • Spleen / cytology
  • Spleen / immunology
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / immunology*


  • Granulocyte Colony-Stimulating Factor
  • Phosphoric Monoester Hydrolases
  • Inositol Polyphosphate 5-Phosphatases