Myeloid-Derived Suppressor Cells Protect Islet Transplants by B7-H1 Mediated Enhancement of T Regulatory Cells

Abstract

Background Side effects of lifetime immunosuppression for cell transplants often outweigh the benefits, therefore, induction of transplant tolerance is needed. We have shown that cotransplantation with myeoid-derived suppressor cells (MDSC) effectively protect islet allografts from rejection without requirement of immunosuppression. This study was to investigate the underlying mechanisms. Methods MDSC were generated by addition of hepatic stellate cells (HpSC) from various stain mice into dendritic cell (DC) culture. The quality of MDSC was monitored by phenotype and function analyses. MDSC mixed with islet allografts were transplanted into diabetic recipients. T cell response was analyzed following transplant by flow and histochemical analyses, and compared to islet alone and islet/DC transplant groups. B7-H1 knockout mice were used to determine the role of B7-H1 on MDSC in regulation of T cell response. Results Cotransplantation with MDSC (not DC) effectively protected islet allografts without requirement of immunosuppression. This is associated with attenuation of CD8 T cells in the grafts and marked expansion of T regulatory (Treg) cells, which contributed to MDSC-induced T cell hyporesponsiveness. Antigen-specific Treg cells were prone to accumulate in lymphoid organs close to the grafts. Both in vitro and in vivo data demonstrated that B7-H1 was absolutely required for MDSC to exert immune regulatory activity and induction of Treg cells. Conclusion The described approach holds great clinical application potential, and may overcome the limitation of requiring chronic administration of immunosuppression in cell transplants. Understanding the underlying mechanisms will facilitate the development of this novel therapeutic strategy.

The Role of Myeloid-Derived Suppressor Cells in Viral Infection

“…MDSC IL-10 production was also implicated in the resolution of inflammation in bacterial pneumonia (120). Another immunosuppressive cytokine, TGF-b, was produced by MDSCs in several murine tumor models (23,87,88,168).…”

Immunological in vivo effects of B7-H1 deficiency

“…The lack of B7-H1 in certain cell types has been shown to have pronounced effects in several disease models, i.e., B7-H1 deficiency increases the protective potential of tolerogenic DC against experimental autoimmune encephalomyelitis (EAE) [17]. B7-H1-deficient MDSC cannot protect islet transplants as successfully as wild-type (WT) MDSC due to their strongly diminished capacity to induce Treg [29]; pancreatic ␤-cells lacking B7-H1 are more susceptible to distraction by specific CD8 T-cells in experimental autoimmune diabetes, [30] and B7-H1-deficient liver sinusoidal endothelial cells are unable to induce CD8 T-cell tolerance in the liver [31]. Another strain of B7-H1KO mice was generated in parallel by Latchman and colleagues, who demonstrated a negative regulation of T-cells in the model of EAE [32].…”

The paradoxical role of tumor-infiltrating immune cells in lung cancer

“…In addition to the effect of ARG-1 and ROS, MDSCs may affect CD8 + T cells via the inhibitory molecules B7-H1 and B7-H4 (50). In addition, MDSCs can enhance immune suppression by directly inducing Tregs through the production of IL-10 and TGF-β or ARG (51,52).…”