Lineage extrinsic and intrinsic control of immunoregulatory cell numbers by SHIP

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 ( T reg) cell numbers, indicating SHIP ‐dependent control of T reg‐cell numbers by a myeloid cell type. Conversely, T ‐lineage specific ablation of SHIP leads to expansion of T reg‐cell numbers, but not expansion of the MDSC compartment, indicating SHIP also has a lineage intrinsic role in limiting T reg‐cell numbers. However, the SHIP ‐deficient myeloid cell that promotes MDSC and T reg‐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 .