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.
Subject(s)
Granulocyte Colony-Stimulating Factor/immunology , Myeloid Cells/immunology , Phosphoric Monoester Hydrolases/immunology , T-Lymphocytes, Regulatory/immunology , Animals , Blotting, Western , Cell Line, Tumor , Cell Lineage , Cell Survival/immunology , Flow Cytometry , Inositol Polyphosphate 5-Phosphatases , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Myeloid Cells/cytology , Phosphoric Monoester Hydrolases/genetics , Spleen/cytology , Spleen/immunology , T-Lymphocytes, Regulatory/cytologyABSTRACT
Regulatory T cells (T(regs)) play a pivotal role in preventing autoimmunity, graft-versus-host disease (GVHD), and organ graft rejection. We previously showed that either germline or induced SH2 domain-containing inositol 5-phosphatase (SHIP) deficiency in the host abrogates GVHD. Here we show that SHIP deficiency promotes an increase of CD4(+)CD25(+)FoxP3(+) T(regs) and CD4(+)CD25(-)FoxP3(+)"naive" T cells in the periphery that display increased CD103, glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR), OX40, and FcgammaRII/III expression. SHIP deficiency does not compromise T(reg) function because SHIP-deficient CD3(+)CD4(+)CD25(+) T(regs) are as suppressive as wild-type (WT) CD3(+)CD4(+)CD25(+) T(reg). Interestingly, like conventional T(regs), SHIP(-/-) CD4(+)CD25(-) T cells are unresponsive to major histocompatibility complex (MHC)-mismatched stimulators and suppress allogeneic responses by T cells in vitro. In addition, SHIP(-/-) CD4(+)CD25(-) T cells mediate reduced lethal GVHD on adoptive transfer to MHC-mismatched hosts. Furthermore, hosts with induced SHIP deficiency exhibit delayed rejection of MHC-mismatched cardiac grafts. Thus, SHIP is required for robust graft-versus-host and host-versus-graft responses by CD4(+) T cell and limits their immunoregulatory capacity. These findings further define the immunosuppressive mechanisms that result from SHIP deficiency and provide additional justification for targeting SHIP in clinical transplantation.
