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Therapeutic use of immunoregulatory cells represents a promising approach for the treatment of uncontrolled immunity. During the last decade, myeloid-derived suppressor cells (MDSC) have emerged as novel key regulatory players in the context of tumor growth, inflammation, transplantation or autoimmunity. Recently, MDSC have been successfully generated in vitro from naive mouse bone marrow cells or healthy human PBMCs using minimal cytokine combinations. In this study, we aimed to evaluate the potential of adoptive transfer of such cells to control auto- and allo-immunity in the mouse. Culture of bone marrow cells with GM-CSF and IL-6 consistently yielded a majority of CD11b+Gr1hi/lo cells exhibiting strong inhibition of CD8+ T cell proliferation in vitro. However, adoptive transfer of these cells failed to alter antigen-specific CD8+ T cell proliferation and cytotoxicity in vivo. Furthermore, MDSC could not prevent the development of autoimmunity in a stringent model of type 1 diabetes. Rather, loading the cells prior to injection with a pancreatic neo-antigen peptide accelerated the development of the disease. Contrastingly, in a model of skin transplantation, repeated injection of MDSC or single injection of LPS-activated MDSC resulted in a significant prolongation of allograft survival. The beneficial effect of MDSC infusions on skin graft survival was paradoxically not explained by a decrease of donor-specific T cell response but associated with a systemic over-activation of T cells and antigen presenting cells, prominently in the spleen. Taken together, our results indicate that in vitro generated MDSC bear therapeutic potential but will require additional in vitro factors or adjunct immunosuppressive treatments to achieve safe and more robust immunomodulation upon adoptive transfer.

We previously described that in a rat model of heart transplantation tolerance was dependent on CD8+CD45RClow Tregs that over-expressed fibrinogen-like protein 2 (FGL2)/fibroleukin. Little is known on the immunoregulatory properties of FGL2. Here we analyzed the transplantation tolerance mechanisms that are present in Lewis 1A rats treated with FGL2. Over-expression of FGL2 in vivo through adenovirus associated virus -mediated gene transfer without any further treatment resulted in inhibition of cardiac allograft rejection. Adoptive cell transfer of splenocytes from FGL2-treated rats with long-term graft survival (> 80 days) in animals that were transplanted with cardiac allografts inhibited acute and chronic organ rejection in a donor-specific and transferable tolerance manner, since iterative adoptive transfer up to a sixth consecutive recipient resulted in transplantation tolerance. Adoptive cell transfer also efficiently inhibited anti-donor antibody production. Analysis of all possible cell populations among splenocytes revealed that B lymphocytes were sufficient for this adoptive cell tolerance. These B cells were also capable of inhibiting the proliferation of CD4+ T cells in response to allogeneic stimuli. Moreover, gene transfer of FGL2 in B cell deficient rats did not prolong graft survival. Thus, this is the first description of FGL2 resulting in long-term allograft survival. Furthermore, allograft tolerance was transferable and B cells were the main cells responsible for this effect.