Expansion of Myeloid Suppressor Cells in SHIP-Deficient Mice Represses Allogeneic T Cell Responses

Abstract

Previously we demonstrated that SHIP−/− mice accept allogeneic bone marrow transplants (BMT) without significant acute graft-vs-host disease (GvHD). In this study we show that SHIP−/− splenocytes and lymph node cells are poor stimulators of allogeneic T cell responses that cause GvHD. Intriguingly, SHIP−/− splenocytes prime naive T cell responses to peptide epitopes, but, conversely, are partially impaired for priming T cell responses to whole Ag. However, dendritic cells (DC) purified from SHIP−/− splenocytes prime T cell responses to allogeneic targets, peptide epitopes, and whole Ag as effectively as SHIP+/+ DC. These findings point to an extrinsic effect on SHIP−/− DC that impairs priming of allogeneic T cell responses. Consistent with this extrinsic effect, we found that a dramatic expansion of myeloid suppressor cells in SHIP−/− mice impairs priming of allogeneic T cells. These findings suggest that SHIP expression or its activity could be targeted to selectively compromise T cell responses that mediate GvHD and graft rejection.

Induced SHIP Deficiency Expands Myeloid Regulatory Cells and Abrogates Graft-versus-Host Disease

“…Hemopoietic stem cells in SHIP Ϫ/Ϫ mice exhibit spontaneous mobilization and reduced BM retention that may reduce the competitive barrier to engraftment by donor hemopoietic stem cells in SHIP-deficient BMT recipients (17). Furthermore, GVHD is reduced in SHIP Ϫ/Ϫ BMT recipients (15) due to a profound expansion of immunoregulatory MySC in secondary lymphoid tissues (7). Although this confluence of genetic abnormalities may contribute to the reduced viability of germline SHIP Ϫ/Ϫ mice (7,22), these studies led us to propose that induction of SHIP deficiency for a short period before allogeneic BMT might enhance engraftment and survival even in settings in which donor and host have a complete MHC mismatch (7,15).…”

“…SHIP's role in signal transduction allows it to regulate cell survival, proliferation, apoptosis, and homeostasis of certain hemopoietic cell types (7,(13)(14)(15)(16), as well as primitive stem cell populations (11,12,17,18). Analysis of SHIP-deficient mice revealed that this protein also has a prominent role in the immune system (7,14,15,19). Significant pathologies have been observed in SHIP Ϫ/Ϫ mice, including splenomegaly and an infiltration of myeloid cells into the lungs that contributes to their reduced life span (13,16,20).…”

“…The SHIP locus also encodes a stem cell-specific isoform called s-SHIP that lacks the Src homology 2 domain and is expressed by pluripotent stem cells and tissue-specific stem cells (11,12). SHIP's role in signal transduction allows it to regulate cell survival, proliferation, apoptosis, and homeostasis of certain hemopoietic cell types (7,(13)(14)(15)(16), as well as primitive stem cell populations (11,12,17,18). Analysis of SHIP-deficient mice revealed that this protein also has a prominent role in the immune system (7,14,15,19).…”

“…Professional APC have been shown to play a critical role in priming allogeneic T cell responses that cause GVHD (1) and solid organ rejection (2). A number of immunoregulatory cell types have been reported to reduce GVHD, including natural suppressor cells (3,4), T regulatory cells (5,6), and Gr1 ϩ myeloid suppressor cells (MySC) (7,8). Strategies to increase the numbers and/or activity of these regulatory cell types are viewed as a means to control GVHD in allogeneic BMT procedures, reduce autoimmune disease, and prevent rejection of solid organ grafts.…”

Role of GM-CSF in tolerance induction by mobilized hematopoietic progenitors

“…Although in the allogeneic setting regulatory T cell (Treg) accumulation triggered by myeloid Gr1 ϩ CD11b ϩ suppressor cells (MSC) reduces acute graft-versus-host disease (GVHD) 1 but instead worsens chronic GVHD, 2 in autoimmune diseases the expansion of Treg is expected to be beneficial. In the experimental model of spontaneous autoimmune diabetes in nonobese diabetic (NOD) mice, we have recently demonstrated 3 that Lin Ϫ Sca1 hi ckit hi Flt3 ϩ CD34 ϩ CD106 ϩ CD127 Ϫ multipotent hematopoietic progenitor cells (HPCs) mobilized to the spleen by a combination of granulocytecolony stimulating factor (G-CSF) and FMS-like tyrosine kinase 3 ligand (Flt3L), have a tolerogenic potential and that their transplantation halts autoimmune diabetes.…”