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

Institut National de la Santé et de la Recherche Médicale, U643, Centre Hospitalier Universitaire Nantes, Institut de Transplantation et de Recherche en Transplantation, Université de Nantes, Faculté de Médecine, Nantes, France.
The Journal of Immunology (Impact Factor: 4.92). 06/2008; 180(12):7898-906. DOI: 10.4049/jimmunol.180.12.7898
Source: PubMed


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(+)CD25(high)FoxP3(+) 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.

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    • "Myeloid cells with suppressive activity inhibit graft-reactive T cell immunity and facilitate induction of regulatory T (Treg) cells, together enabling the induction of transplantation tolerance (Dugast et al., 2008; Garcia et al., 2010; Zhang et al., 2008). An emerging consensus is that myeloid cells with immune regulatory function are contained within a population of CD11b + mononuclear cells that express the myeloid differentiation antigen Gr-1 (Bronte et al., 2000; Bronte et al., 1998). "
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    ABSTRACT: Tissue effector cells of the monocyte lineage can differentiate into different cell types with specific cell function depending on their environment. The phenotype, developmental requirements, and functional mechanisms of immune protective macrophages that mediate the induction of transplantation tolerance remain elusive. Here, we demonstrate that costimulatory blockade favored accumulation of DC-SIGN-expressing macrophages that inhibited CD8(+) T cell immunity and promoted CD4(+)Foxp3(+) Treg cell expansion in numbers. Mechanistically, that simultaneous DC-SIGN engagement by fucosylated ligands and TLR4 signaling was required for production of immunoregulatory IL-10 associated with prolonged allograft survival. Deletion of DC-SIGN-expressing macrophages in vivo, interfering with their CSF1-dependent development, or preventing the DC-SIGN signaling pathway abrogated tolerance. Together, the results provide new insights into the tolerogenic effects of costimulatory blockade and identify DC-SIGN(+) suppressive macrophages as crucial mediators of immunological tolerance with the concomitant therapeutic implications in the clinic. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Jun 2015 · Immunity
    • "MDSCs of rat origin were first described as CD11b/c + and HIS48 + cells in a T9 glioma model [8]. CD172a (SIRPa), TGF-b, iNOS or arginase expressions were also reported for rat and mice MDSCs, and NO À was found to be responsible for the suppressive activity of glioma infiltrating rat MDSCs [9] [10] [11] [12]. Here we employed Rp-1 antibody discrimination of granulocytic cells from monocytic ones and introduced a new classification for rat monocytes depending on HIS48 positivity. "
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    ABSTRACT: Limited knowledge is available on myeloid derived suppressor cells (MDSCs) of rat origin. We examined the myeloid cells from peripheral blood, bone marrow and spleens of healthy and mammary tumor bearing rats employing a novel immunophenotyping strategy with CD172a, HIS48, and Rp-1 antibodies. We addressed rat granulocytes by Rp-1 positivity and used HIS48 in discrimination of two mononuclear cell subsets. An expansion of granulocyte numbers was detected in peripheral blood and spleens of mammary tumor-bearing animals. The purified granulocytes were able to impair antigen-specific helper T-cell proliferation, and therefore nominated as granulocytic MDSCs of this rat tumor model. HIS48(+) mononuclear cell numbers were also increased in the blood and spleens of mammary tumor bearing rats with a lower MHC class II positivity. Despite the lack of an antigen specific suppression of CD4(+) T cells, HIS48(+) monocytes resemble monocytic MDSCs with their inflammatory phenotype. Together, these results provide evidence for the existence and phenotypic characterization of a granulocytic MDSC subset in a rat model of mammary carcinoma. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Feb 2015 · Cellular Immunology
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    • "Combined the fact that Tregs were present in high numbers and fully functional with the phenomenon that effector T cells mediated-inflammation persisted in vivo, we supposed that some inflammatory-related factors caused resistance of effector T cells to suppression that contributed to the ongoing autoimmune response. It has been reported that IMC accumulation occurs in several autoimmune diseases, but there is still an ongoing debate that these cells play a pro-inflammatory or anti-inflammatory role in autoimmune diseases [20], [21]. We found that the frequency of IMC significant increased in the spleen of atherosclerotic Apo E−/− mice. "
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    ABSTRACT: Accumulating evidence indicates that both defects in Treg numbers and/or function as well as resistance of effector T cells to suppression may contribute to the development of human chronic inflammatory diseases. However, which mechanism involved in the progression of atherosclerosis remains unclear. In this study, we evaluated the production and function of CD4+ inflammatory and regulatory T cells in atherosclerosis-prone mice. We found that the hyperactivity and unresponsiveness to Treg-mediated suppression of inflammatory CD4+ T cells occurred in the progression of atherosclerosis, though Treg cells were present in very large numbers and fully functional. We further found that Gr-1+CD11b+ immature myeloid cells were significantly accumulated in atherosclerotic Apo E-/- mice, and they promoted resistance of inflammatory CD4+ T cells to Treg-mediated suppression in vitro and in vivo. we further confirmed that Gr-1+CD11b+ immature myeloid cells produced high level of interleukin 6 which was at least partially responsible for inducing unresponsiveness of inflammatory CD4+ T cells to suppression via activation of Jak/Stat signaling pathway. Taken together, these findings might provide new insights to explore potential targets for immune therapeutic intervention in atherosclerosis.
    Full-text · Article · Sep 2014 · PLoS ONE
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