In Vivo Induction of Myeloid Suppressor Cells and CD4⁺Foxp3⁺T Regulatory Cells Prolongs Skin Allograft Survival in Mice

Abstract

Natural CD4+ Foxp3 + T regulatory (Treg) cells can promote transplantation acceptance across major histocompatibility complex (MHC) barriers, while myeloid-derived suppressor cells (MDSCs) inhibit effector Tcell responses in tumor-bearing mice. One outstanding issue is whether combining the potent suppressive function of MDSCs with that of Treg cells might synergistically favor graft tolerance. In the present study, we evaluated the therapeutic potential of MDSCs and natural Treg cells in promoting allograft tolerance in mice by utilizing immunomodulatory agents to expand these cells in vivo. Upon administration of recombinant human granulocyte-colony stimulating factor (G-CSF; Neupogen), or interleukin-2 complex (IL-2C), Gr-1 + CD11b + MDSCs or CD4 + Foxp3 + Treg cells were respectively induced at a high frequency in the peripheral lymphoid compartments of treated mice. Interestingly, induced MDSCs exhibited a more potent suppressive function in vitro when compared to MDSCs from naive mice. Furthermore, in vivo coadministration of Neupogen and IL-2C induced MDSCs at percentages that were higher than those seen when either agent was administered alone, suggesting an additive effect of the two drugs. Although treatment with either IL-2C or Neupogen led to a significant delay of MHC class II disparate allogeneic donor skin rejection, the combinatorial treatment was superior to either alone. Importantly, histological assessment of surviving grafts revealed intact morphology and minimal infiltrates at 60 days posttransplant. Collectively, our findings demonstrate that concurrent induction of MDSCs and Tregs is efficacious in downmodulating alloreactive T-cell responses in a synergistic manner and highlight the therapeutic potential of these naturally occurring suppressive leukocytes to promote transplantation tolerance.

Targeted depletion of an MDSC subset unmasks pancreatic ductal adenocarcinoma to adaptive immunity

“…18 However, since the grafts comprised cell lines from a heterologous (mixed) genetic background, or from cells virally transduced to exogenously express foreign proteins, the antitumour activity of endogenous CD8 T cells in this setting was probably due, at least in part, to recognition of minor histocompatibility alloantigens or foreign epitopes. These findings are consistent with previous work demonstrating that myeloid-derived suppressor cells (MDSC) can prevent graft rejection, [19][20][21][22] but leave unaddressed the potential therapeutic benefit of this strategy in a clinical oncology setting. Furthermore, it remains unclear if disrupting cancer-associated myeloid cells would have an impact on established, autochthonous pancreas cancers.…”

Phenotype, development, and biological function of myeloid-derived suppressor cells

“…C Gr-1 C MDSCs from G-CSF-treated mice, 16 supporting the hypothesis that the systemic recruitment and trafficking result in increased frequencies at multiple peripheral sites. Movahedi et al presented …”

“…43 The administration of recombinant G-CSF or IL-2 in mice results in the accumulation of Gr-1 C CD11b C MDSCs and Treg cells in the peripheral lymphoid organs, which significantly delays allogeneic donor skin rejection. 16 It was reported that IL-1R deficiency delays MDSC accumulation in tumorbearing mice. 44 In contrast, excessive inflammation in IL-1R antagonist-deficient mice promotes the accumulation of MDSCs with enhanced immunosuppressive activity.…”

Control of Transplant Tolerance and Intragraft Regulatory T Cell Localization by Myeloid-Derived Suppressor Cells and CCL5

“…Indeed, transplant tolerance is mostly associated with the action of regulatory T cells (Treg) (14) working in synergy with MDSC (15,16) and other suppressive cell types, such as monocytes (17), NK cells (18), plasmacytoid dendritic cells (19)(20)(21)(22), or immature dendritic cells (23). However, the mechanisms involved in this cooperation are not well understood.…”