Lineage extrinsic and intrinsic control of immunoregulatory cell numbers by SHIP

Abstract

Summary We previously showed that germline or induced SHIP-deficiency expands immunoregulatory 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 expansion of both myeloid-derived suppressor cell (MDSC) and regulatory T cell (Treg) numbers indicating SHIP-dependent control of Treg numbers by a myeloid cell type. Conversely, T lineage specific ablation of SHIP leads to expansion of Treg numbers, but not expansion of the MDSC compartment, indicating SHIP also has a lineage intrinsic role in limiting Treg numbers. However, the SHIP-deficient myeloid cell that promotes MDSC and Treg 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.

Host miR155 Promotes Tumor Growth through a Myeloid-Derived Suppressor Cell–Dependent Mechanism

“…We also noted increased SHIP-1 expression in miR-155 −/− MDSCs. Interestingly, SHIP-1 was recently reported as a target of miR-155 specifically in MDSC expansion (17), consistent with the previous observation that myeloid-specific ablation of SHIP resulted in an increase in MDSC numbers (57). However, the prior study did not examine the importance of MDSC miR-155 status in tumor growth (17).…”

Lineage-specific regulation of allergic airway inflammation by the lipid phosphatase Src homology 2 domain–containing inositol 5-phosphatase (SHIP-1)

“…Our data support previous findings and suggest that although deletion of Ship1 in either the myeloid or early lymphoid lineages leads to increased Treg cell frequencies, deletion at later stages of lymphocyte development does not affect Treg cell numbers. 17,33,34 Although in vitro experiments have suggested a role for SHIP-1 in regulating DC development, maturation, and T-cell interactions, its role in vivo has not been explored. [18][19][20] In this study we used targeted deletion in DCs to evaluate SHIP-1's function in the development of adaptive immune responses.…”

Phenotype, development, and biological function of myeloid-derived suppressor cells

“…One study showed that myeloid-specific ablation of SHIP leads to the expansion of both MDSCs and Treg cell numbers, indicating a SHIP-dependent regulation of Treg cells by a myeloid cell type. 79 Meanwhile, G-CSF levels are profoundly increased in SHIP ¡/¡ mice, suggesting that this myelopoietic growth factor can promote MDSC expansion in a cell-extrinsic manner. Thus, SHIP controls MDSC numbers, in part, by limiting production of the myelopoietic growth factor G-CSF.…”

“…Thus, SHIP controls MDSC numbers, in part, by limiting production of the myelopoietic growth factor G-CSF. 79 In addition, SHIP-1-regulated MDSC expansion and function may contribute to pancreatic tumor progression. 80 …”