1 MDSC. MDSC common myeloid progenitor CMP CMP CMP myeloid-derived suppressor cells MDSC MDSC MDSC MDSC. CD11b + Gr1 + Ly6G + Ly6C low

Transcript

1 Chin J Transplant Electronic Edition May 2012Vol 6No. 2 吴婷婷 赵勇 MDSC T MDSC MDSC MDSC MDSC T T MDSC Regulation of myeloid derived suppressor cells and its role in transplantation WU Ting-ting ZHAO Yong. State Key Laboratory of Biomembrane and Membrane BiotechnologyInstitute of Zoology Chinese Academy of SciencesBeijing China Corresponding authorzhao Yong zhaoy@ ioz. ac. cn Abstract Myeloid derived suppressor cells MDSCrepresent a heterogenic population of immature myeloid cells and are characterized by a strong ability to suppress various T cell functions. The molecular mechanism regulating MDSC differentiation includes many growth factorscytokines transcription factorsand several signaling pathways. These factors are critically important for the development of the effective therapeutic strategies to induce these cells in transplantation. Hereinwe briefly summarized the characterization of MDSCthe molecular mechanisms that regulate the development of MDSCand the role of MDSC in transplantation. Key words Myeloid-derived suppressor cells Regulation Immune tolerance Molecular biology 1 MDSC MDSC common myeloid progenitorcmp CMP CMP myeloid-derived suppressor cellsmdsc MDSC MDSC MDSC DOI /cma. j. issn CD11b + Gr CB zhaoy@ ioz. ac. cn Lin-HLA-DR-CD33 + CD11b + CD14 - CD33 + MDSC CD11b + Ly6G - Ly6C high CD11b + Ly6G + Ly6C low T

2 Chin J Transplant Electronic Edition May 2012Vol 6No MDSC CMP MDSC G-CSF F4 /80 CD115 / G-CSF CD124 CD80 T MDSC MDSC G-CSF MDSC IL-6 3 IL-1β IL-17 κb 1 nuclear factor κb NF-κB 3-5 G-CSF T 2 3- T signal transducers and activators of transcription IL-10 TGF-β1 STAT3 MDSC 6 T MDSC M-CSF NK M-CSF 2 MDSC M-CSF CD115 MDSC MDSC 7 M-CSF MDSC M-CSF MDSC M-CSF MDSC MDSC 8 MDSC 2. 1 MDSC granulocyte- MDSC VEGF - VEGF 5 macrophage colony stimulating factorgm-csf VEGF granulocyte-colony stimulating factor G-CSF macrophagecolony stimulating factorm-csf 1 VEGF VEGF vascular endothelial growth factorvegf GM-CSF NF-κB 11 GM-CSF VEGF 2 CD11b + CMP Gr1 + MDSC B 12 GM-CSF VEGF MDSC GM-CSF T MDSC GM-CSF MDSC IL-1β 1 GM-CSF IL-1β IL-1β 2 GM-CSF IL-1β MDSC IL-10 M-CSF 9 Gr1 + B 10 MDSC G-CSF IL-1β MDSC G-CSF 14 IL-1β 4T1

3 Chin J Transplant Electronic Edition May 2012Vol 6No. 2 MDSC G 1 S IL-6 IL-1β C /EBPα CMP IL-6 MDSC 15 IL-1β 23 C /EBPβ MDSC IL-1 NF-κB MDSC IL-6 MDSC C /EBPβ C /EBPβ CD11b + Gr1 + C /EBPβ MDSC IL-6 IL-6 C /EBPβ MDSC Arg1 CCAAT CCAAT / enhancer binding proteinsc /EBPβ C /EBP IL-6 GM-CSF MDSC NF-κB p50 17 C /EBPα IFN-γ T 1 IFN-γ PU. 1 IFN-γ - / - C /EBP PU. 1 T PU IFN-γ - CD11 F4 /80 25 IFN-γ CMP - MDSC IFN-γ PU. 1 CD11b - Gr1 + MDSC 19 PU MDSC C /EBPα PU. 1 IFN-γ 20 IFN-γ IFN-γ GM-CSF IL-6 M-CSF 27 MDSC MDSC IFN-γ STAT MDSC Janus /STAT 21 IFN-γ MDSC T STAT MDSC STAT3 STAT3 CMP CMP MDSC MDSC STAT3 C /EBP PU. 1 STAT GM-CSF IL-6 MDSC C /EBPβ p50 G-CSF STAT1 STAT5 STAT6 MDSC MDSC MDSC STAT3 VEGF C /EBP STAT3 30 C /EBP STAT3 C /EBPα MDSC 31 E2F1 STAT3

4 Chin J Transplant Electronic Edition May 2012Vol 6No MDSC exosome 72 STAT3 MDSC 32 STAT3 MDSC STAT3 S100A9 S100A8 MDSC STAT3 MDSC MDSC CβⅡ STAT3 CβⅡ Notch MDSC MDSC Notch 35 STAT3 Notch1 RNA C /EBPβ C /EBPβ Notch MDSC 36 MDSC STAT3 STAT3 Notch 2 p47phox B 47 Notch gp91phox MDSC B 37 STAT3 MDSC 48 Notch MDSC STAT3 CXCL1 CXCL2 MDSC 38 STAT1 STAT5 STAT6 MDSC Wnt-β STAT1 IFN-γ IL-1β 49 β 1 MDSC STAT1 MDSC 1 β GM-CSF 1 T IL-4 CMP MDSC 50 CMP 39 STAT1 Wnt-β MDSC MDSC 40 STAT5 MDSC MDSC STAT6 IL-4 IL-13 CD124 CD124 MDSC MDSC 1 TGF-β1 STAT MDSC T 41 STAT6 MDSC 42 MDSC MDSC S100A9 S100A NF-κB MDSC STAT3 NF-κB MDSC S100A9 S100A8 Toll IL-1R NF-κB MDSC MDSC S100A9 MDSC 44 NF-κB MDSC S100A9 33 C /EBPα MDSC MDSC Toll S100A9-S100A8 88 myeloid differentiation 88 NF-κB 1 triggering 33 receptor expressed on myeloid cells 1 S100A9 S100A8 MDSC N- NF-κB MDSC MDSC MDSC NF-κB Wnt-β catenin MDSC 1

5 Chin J Transplant Electronic Edition May 2012Vol 6No. 2 E 2 prostaglandin E 2 PGE 2 2cyclooxygenase-2 Cox2 p38 3- SH2 PPARγC SH2 domain containing 5'-inosi-tol phosphatase MDSC T 58 SHIP γ RNA MDSC peroxisome proliferator-activated receptor-γpparγ RNA MDSC RNA MDSC CD11b + Gr PGE 2 Cox2 MDSC RNA MDSC PGE 2 MDSC T RNA mir-223 mir-17-5p mir-20a PGE 2 MDSC PGE 2 EP4 51 MDSC mir-223 MDSC PGE 2 MDSC 2 myocyte enhancer factor 2 Fas 3LL Lewis p38 PGE 2 MDSC MDSC STAT3 PEG 2 Cox2 MDSC MDSC PGE MDSC MDSC PGE 2 2 CD28 MDSC 53 MDSC MDSC PGE 2 Cox2 CD1a + CD14 + CD33 + CD34 + MDSC 54 MDSC PGE 2 61 CD40 Cox2 MDSC CD11b + Gr1 + CD115 + MDSC IL-33 Cox2 PGE 2 MDSC IL-33 MDSC 62 2 / SHIP MDSC HLA-G MDSC SHIP MDSC 2 MDSC 1 SHIP - / N- MDSC Ⅲlacto-N-fucopentaose Ⅲ T 56 MDSC PD-L1 SHIP - / - 64 GM-CSF IL MDSC PPARγ MDSC STAT3 NF-κB Erk1 /2 MDSC mir-223 MDSC 59 mir-17-5p mir-20a PPARγ CD14 + CD14 - MDSC N- IL-1β IL-2 IL T TNF-α IL CMP - G-CSF MDSC PPARγ CD11b + Ly6G + T

6 Chin J Transplant Electronic Edition May 2012Vol 6No MDSC inhibitor targets effector functions and T T MDSC hematopoietic stem cells J T MDSC B7-H1 T 68 MDSC CCL5 T 69 4 MDSC MDSC factor J. J Immunol MDSC Cancer Res MDSC 3670 MDSC IL-1beta-secreting cells J MDSC MDSC suppressor cells and limits tumor progression J 1 Serafini PCarbley RNoonan KAet al. High-dose granulocytemacrophage colony-stimulating factor-producing vaccines impair the immune response through the recruitment of myeloid suppressor cells J. Cancer Res Nishijima INakahata TWatanabe Set al. Hematopoietic and lymphopoietic responses in human granulocyte-macrophage colonystimulating factor GM-CSFreceptor transgenic mice injected with human GM-CSF J. Blood Cuenca AGDelano MJKelly-Scumpia KMet al. A paradoxical role for myeloid-derived suppressor cells in sepsis and traumaj. Mol Med He RLZhou JHanson CZet al. Serum amyloid A induces G-CSF expression and neutrophilia via Toll-like receptor 2J. Blood He DLi HYusuf Net al. IL-17 promotes tumor development through the induction of tumor promoting microenvironments at tumor sites and myeloid-derived suppressor cellsj. J Immunol Panopoulos ADWatowich SS. Granulocyte colony-stimulating factormolecular mechanisms of action during steady state and emergency hematopoiesisj. Cytokine Huang BPan PYLi Qet al. Gr-1 + CD115 + immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing hostj. Cancer Res Irvine KMBurns CJWilks AFet al. A CSF-1 receptor kinase inhibits pro-inflammatory cytokine production from murine macrophage populations J. FASEB J Zhou ZFrench DLMa Get al. Development and function of myeloid-derived suppressor cells generated from mouse embryonic and. Stem Cells Gerber HPFerrara N. The role of VEGF in normal and neoplastic hematopoiesis J. J Mol Med Berl Kusmartsev SGabrilovich DI. Effect of tumor-derived cytokines and growth factors on differentiation and immune suppressive features of myeloid cells in cancerj. Cancer Metastasis Rev Larrivée BPollet IKarsan A. Activation of vascular endothelial growth factor receptor-2 in bone marrow leads to accumulation of myeloid cells role of granulocyte-macrophage colony-stimulating 13 Ozao-Choy JMa GKao Jet al. The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immune-based cancer therapiesj. 14 Song XKrelin YDvorkin Tet al. CD11b + /Gr-1 + immature myeloid cells mediate suppression of T cells in mice bearing tumors of. J Immunol Bunt SKYang LSinha Pet al. Reduced inflammation in the tumor microenvironment delays the accumulation of myeloid-derived. Cancer Res Tu SBhagat GCui Get al. Overexpression of interleukin-1beta induces gastric inflammation and cancer and mobilizes myeloidderived suppressor cells in micej. Cancer Cell Marigo IBosio ESolito Set al. Tumor-induced tolerance and immune suppression depend on the C / EBPbeta transcription factor J. Immunity Konieczny BTDai ZElwood ETet al. IFN-gamma is critical for long-term allograft survival induced by blocking the CD28 and CD40 ligand T cell costimulation pathways J. J Immunol Greifenberg VRibechini ERssner Set al. Myeloid-derived suppressor cell activation by combined LPS and IFN-gamma treatment impairs DC developmentj. Eur J Immunol Garcia MRLedgerwood LYang Yet al. Monocytic suppressive cells mediate cardiovascular transplantation tolerance in micej. J Clin Invest Rssner SVoigtlnder CWiethe Cet al. Myeloid dendritic cell precursors generated from bone marrow suppress T cell responses via cell contact and nitric oxide production in vitroj. Eur J Immunol Gallina GDolcetti LSerafini Pet al. Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8 + T cells J. J Clin Invest Zhang PIwasaki-Arai JIwasaki Het al. Enhancement of hematopoietic stem cell repopulating capacity and self-renewal in the absence of the transcription factor C /EBP alphaj. Immunity

7 Chin J Transplant Electronic Edition May 2012Vol 6No Wang DPaz-Priel IFriedman AD. NF-kappa B p50 regulates C / EBP alpha expression and inflammatory cytokine-induced neutrophil production J. J Immunol Ito TNishiyama CNakano Net al. Roles of PU. 1 in monocyteand mast cell-specific gene regulationpu. 1 transactivates CIITA piv in cooperation with IFN-gammaJ. Int Immunol Iwasaki HSomoza CShigematsu Het al. Distinctive and indispensable roles of PU. 1 in maintenance of hematopoietic stem cells and their differentiation J. Blood Iwama AZhang PDarlington GJet al. Use of RDA analysis of knockout mice to identify myeloid genes regulated in vivo by PU. 1 and C /EBPalphaJ. Nucleic Acids Res Nefedova YHuang MKusmartsev Set al. Hyperactivation of STAT3 is involved in abnormal differentiation of dendritic cells in cancer J. J Immunol Nefedova YNagaraj SRosenbauer Aet al. Regulation of dendritic cell differentiation and antitumor immune response in cancer by pharmacologic-selective inhibition of the janus-activated kinase 2 / signal transducers and activators of transcription 3 pathwayj. Cancer Res Kujawski MKortylewski MLee Het al. Stat3 mediates myeloid cell-dependent tumor angiogenesis in mice J. J Clin Invest Xin HZhang CHerrmann Aet al. Sunitinib inhibition of Stat3 induces renal cell carcinoma tumor cell apoptosis and reduces immunosuppressive cellsj. Cancer Res Chalmin FLadoire SMignot Get al. Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells J. J Clin Invest Cheng PCorzo CALuetteke Net al. Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein J. J Exp Med Sinha POkoro CFoell Det al. Proinflammatory S100 proteins regulate the accumulation of myeloid-derived suppressor cellsj. J Immunol Farren MRCarlson LMLee KP. Tumor-mediated inhibition of dendritic cell differentiation is mediated by down regulation of protein kinase C betaⅡexpression J. Immunol Res Zhang HNguyen-Jackson HPanopoulos ADet al. STAT3 controls myeloid progenitor growth during emergency granulopoiesis J. Blood Corzo CACotter MJCheng Pet al. Mechanism regulating reactive oxygen species in tumor-induced myeloid-derived suppressor cells J. J Immunol Sander LESackett SDDierssen Uet al. Hepatic acute-phase proteins control innate immune responses during infection by promoting myeloid-derived suppressor cell functionj. J Exp Med Kusmartsev SGabrilovich DI. STAT1 signaling regulates tumorassociated macrophage-mediated T cell deletionj. J Immunol Movahedi KGuilliams MVan den Bossche Jet al. Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activityj. Blood Ko JSRayman PIreland Jet al. Direct and differential suppression of myeloid-derived suppressor cell subsets by sunitinib is compartmentally constrainedj. Cancer Res Munera VPopovic PJBryk Jet al. Stat 6-dependent induction of myeloid derived suppressor cells after physical injury regulates nitric oxide response to endotoxin J. Ann Surg Terabe MMatsui SPark JMet al. Transforming growth factor-beta production and myeloid cells are an effector mechanism through which CD1d-restricted T cells block cytotoxic T lymphocyte-mediated tumor immunosurveillanceabrogation prevents tumor recurrence J. J Exp Med Delano MJScumpia POWeinstein JSet al. MyD88-dependent expansion of an immature GR-1+ CD11b+ population induces T cell suppression and Th2 polarization in sepsisj. J Exp Med Martino ABadell EAbadie Vet al. Mycobacterium bovis bacillus Calmette-Guérin vaccination mobilizes innate myeloid-derived suppressor cells restraining in vivo T cell priming via IL-1Rdependent nitric oxide productionj. J Immunol Liu YXiang XZhuang Xet al. Contribution of MyD88 to the tumor exosome-mediated induction of myeloid derived suppressor cells J. Am J Pathol Carlesso NAster JCSklar Jet al. Notch1-induced delay of human hematopoietic progenitor cell differentiation is associated with altered cell cycle kinetics J. Blood Schroeder TJust U. Notch signalling via RBP-J promotes myeloid differentiation J. EMBO J Scheller MHuelsken JRosenbauer Fet al. Hematopoietic stem cell and multilineage defects generated by constitutive beta-catenin activation J. Nat Immunol Poh TWBradley JMMukherjee Pet al. Lack of Muc1-regulated beta-catenin stability results in aberrant expansion of CD11b + Gr1 + myeloid-derived suppressor cells from the bone marrowj. Cancer Res Rodriguez PCHernandez CPQuiceno Det al. Arginase Ⅰ in myeloid suppressor cells is induced by COX-2 in lung carcinoma J. J Exp Med Zhang YLiu QZhang Met al. Fas signal promotes lung cancer growth by recruiting myeloid-derived suppressor cells via cancer cellderived PGE 2 J. J Immunol Sinha PClements VKFulton AMet al. Prostaglandin E 2 promotes tumor progression by inducing myeloid-derived suppressor cellsj. Cancer Res Obermajer NMuthuswamy RLesnock Jet al. Positive feedback between PGE 2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cellsj. Blood Eruslanov EDaurkin IOrtiz Jet al. Pivotal advancetumormediated induction of myeloid-derived suppressor cells and M2- polarized macrophages by altering intracellular PGE2catabolism in myeloid cells J. J Leukoc Biol

8 Chin J Transplant Electronic Edition May 2012Vol 6No Ghansah TParaiso KHHighfill Set al. Expansion of myeloid suppressor cells in SHIP-deficient mice represses allogeneic T cell responses J. J Immunol Wang JWHowson JMGhansah Tet al. Influence of SHIP on the NK repertoire and allogeneic bone marrow transplantation J. Science Wu LYan CCzader Met al. Inhibition of PPARγ in myeloidlineage cells induces systemic inflammation immunosuppressionand tumorigenesis J. Blood Liu QZhang MJiang Xet al. mir-223 suppresses differentiation of tumor-induced CD11b + Gr1 + myeloid-derived suppressor cells from bone marrow cellsj. Int J Cancer Zhang MLiu QMi Set al. Both mir-17-5p and mir-20a alleviate suppressive potential of myeloid-derived suppressor cells by modulating STAT3 expression J. J Immunol Dugast ASHaudebourg TCoulon Fet al. Myeloid-derived suppressor cells accumulate in kidney allograft tolerance and specifically suppress effector T cell expansion J. J Immunol Brunner SMSchiechl GFalk Wet al. Interleukin-33 prolongs allograft survival during chronic cardiac rejectionj. Transpl Int Zhang WLiang SWu Jet al. Human inhibitory receptor immunoglobulin-like transcript 2 amplifies CD11b + Gr1 + myeloidderived suppressor cells that promote long-term survival of allografts J. Transplantation Dutta PHullett DARoenneburg DAet al. Lacto-N-fucopentaose Ⅲa pentasaccharideprolongs heart transplant survival J. Transplantation Highfill SLRodriguez PCZhou Qet al. Bone marrow myeloidderived suppressor cells MDSCsinhibit graft-versus-host disease GVHD via an arginase-1-dependent mechanism that is upregulated by interleukin-13 J. Blood Hock BDMackenzie KACross NBet al. Renal transplant recipients have elevated frequencies of circulating myeloid-derived suppressor cellsj. Nephrol Dial Transplant Luyckx ASchouppe ERutgeerts Oet al. G-CSF stem cell mobilization in human donors induces polymorphonuclear and mononuclear myeloid-derived suppressor cellsj. Clin Immunol Chou HSHsieh CCCharles Ret al. Myeloid-derived suppressor cells protect islet transplants by B7-H1 mediated enhancement of T regulatory cells J. Transplantation Dilek NPoirier NUsal Cet al. Control of transplant tolerance and intragraft regulatory T cell localization by myeloid-derived suppressor cells and CCL5 J. J Immunol Sinha PClements VKOstrand-Rosenberg S. Interleukin-13- regulated M2 macrophages in combination with myeloid suppressor cells block immune surveillance against metastasisj. Cancer Res 吴婷婷, 赵勇. 髓源性抑制细胞的调控及其在移植免疫中的作用 [J /CD]. 中华移植杂志 : 电子版,2012,6( 2) :