Myeloid-Derived Suppressor Cells Accumulate in Kidney Allograft Tolerance and Specifically Suppress Effector T Cell Expansion

Abstract

The immune tolerance to rat kidney allografts induced by a perioperative treatment with anti-CD28 Abs is associated with a severe unresponsiveness of peripheral blood cells to donor Ags. In this model, we identified an accumulation in the blood of CD3−class II−CD11b+CD80/86+ plastic-adherent cells that additionally expressed CD172a as well as other myeloid markers. These cells were able to inhibit proliferation, but not activation, of effector T cells and to induce apoptosis in a contact-dependent manner. Their suppressive action was found to be under the control of inducible NO synthase, an enzyme also up-regulated in tolerated allografts. Based on these features, these cells can be defined as myeloid-derived suppressor cells (MDSC). Interestingly, CD4+CD25highFoxP3+ regulatory T cells were insensitive in vitro to MDSC-mediated suppression. Although the adoptive transfer of MDSC failed to induce kidney allograft tolerance in recently transplanted recipients, the maintenance of tolerance after administration of anti-CD28 Abs was found to be dependent on the action of inducible NO synthase. These results suggest that increased numbers of MDSC can inhibit alloreactive T cell proliferation in vivo and that these cells may participate in the NO-dependent maintenance phase of tolerance.

Rapamycin Prolongs Cardiac Allograft Survival in a Mouse Model by Inducing Myeloid-Derived Suppressor Cells

“…Although previous reports show that adoptive transfer of MDSCs protects transplanted islet cells from rejection (32), rat kidney transplantation models (6) failed to show that MDSCs extend graft survival. Given the difference between these models, and the fact that the suppressive activity of MDSCs is contact-dependent, it appears that transferred MDSCs must migrate into and remain within an allograft to be effective.…”

“…Thus, it is likely that these cells also interact with anti-Gr-1 antibodies and L-NMMA. However, administration of anti Gr-1 antibodies (RB6-8C5) or L-NMMA is a commonly used technique to deplete MDSC populations and inhibit MDSC function in vivo (4)(5)(6)8,12,33). Thus, in our experiment, systemic administration of anti-Gr-1 antibodies and L-NMMA was used to examine the extent to which MDSCs contribute to the prolongation of cardiac allograft survival in rapamycin-treated recipients.…”

“…This location may fully exhibit MDSC function; indeed, Dugast et al (6) reported that MDSCs fulfill their functions in a contact-dependent manner. Immunohistochemical analysis of cardiac tissue sections revealed that both Gr-1/CD11b-expressing and macrophage-like cells were present in the subintimal space in graft vessels and in the subendocardial layer of transplanted cardiac tissue ( Figure 6).…”

“…Several studies have examined the relationship between allograft survival and the presence of immune cells by either removing specific cells from the recipient or by adoptively transferring cells into the recipient (1,2). Growing evidence suggests that myeloid-derived suppressor cells (MDSCs) play a crucial role in promoting cancer (3), suppressing autoimmune disease (4) and organ transplant rejection (5)(6)(7)(8). Thus, it would be interesting to examine the mechanisms by which MDSCs suppress immunological rejection and to identify the specific molecules involved; such knowledge could then be applied to clinical organ transplantation.…”

Selective CD28 Antagonist Blunts Memory Immune Responses and Promotes Long-Term Control of Skin Inflammation in Nonhuman Primates

“…Selective CD28 blockade was described to induce immune tolerance and regulatory cells in transplant experimental models (14)(15)(16)(17)(18). We previously described that selective monovalent CD28 versus CD80/86 antagonists differentially control human effector and regulatory memory T cell activation in vitro at the immune synapse level (19).…”