*Purpose: Myeloid-derived suppressor cells (MDSC) are a naturally occurring, heterogeneous population of highly immunosuppressive CD11b⁺GR-1⁺ myeloid cells that expand in response to inflammatory conditions. Although MDSCs develop after transplantation, it is unknown how these cells target transplanted grafts. In this study, we investigated the hypothesis that MDSC develop after vascularized, solid organ transplantation and migrate to the allograft.

*Methods: Kidney and cardiac transplants were performed between C57BL/6 and BALB/c mice, without immunosuppression. Development of endogenous MDSC was assessed by flow cytometry or immunohistochemistry for CD11b⁺Gr-1⁺ cells in blood, spleen, and graft. Co-culture assays were performed to assess the ability of MDSC to suppress T cell function. GFP⁺MDSCs were adoptively transferred to transplant recipients by intravenous injection after transplantation, and spleens and grafts were examined for migration of exogenous MDSC at time points thereafter.

*Results: CD11b+Gr-1+ cells were significantly expanded in the spleens and peripheral blood of transplanted mice. Splenic CD11b⁺Gr-1⁺ MDSCs isolated from transplanted mice inhibited anti-CD3-stimulated CD4 T cell proliferation in vitro. MDSCs were detected in both allogeneic cardiac and kidney grafts, whereas they were not detected in syngeneic grafts or in naïve organs. To determine if adoptively transferred MDSCs would also migrate to the graft, and to distinguish these from autologous MDSCs, we developed LLC1 lung tumors in transgenic GFP mice (tgCAG-EGFP C57BL/6J, JAX #006567) because LLC1 tumors lead to marked increases in MDSCs. Next, GFP+CD11b+Gr-1+ MDSCs were isolated 3 weeks after tumor development and adoptively transferred on the day of transplantation. Both adoptively transferred MDSCs and endogenous MDSCs were detected in the allografts and spleens 4 days post transfer. GFP+ MDSCs were visualized using fluoroscopic microscopy. Adoptive transfer of MDSCs alone increased graft survival up to 9.5 days from 6 days in control animals without MDSC transfer (p<0.0001). Graft survival increased further with added doses of adoptively transferred MDSCs and when MDSCs were pharmacologically expanded.

*Conclusions: Adoptively transferred MDSCs homed to the graft and prolonged allograft survival. Our data suggest that MDSCs can target transplanted allografts and may be exploited to control T cell responses. These data have important implications for investigations of both immunosuppression minimization and tolerance induction.

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