Skip to main content

Advertisement

SpringerLink
Log in

Lung myeloid-derived suppressor cells and regulation of inflammation

  • UNIVERSITY OF PITTSBURGH IMMUNOLOGY 2011
  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

Myeloid-derived suppressor cells (MDSCs) have been investigated largely in the context of tumor progression. In contrast to the negative connotation of MDSCs in cancer immunity, our laboratory has recently reported on the development and role of pulmonary MDSC-like cells (CD11b+Gr1intF4/80+) in the regulation of allergic airway inflammation. These regulatory cells were expanded in a TLR4/MyD88-dependent manner and were both phenotypically and morphologically similar to those described in the tumor microenvironment. Although bacterial lipopolysaccharide (LPS) was initially described as an adjuvant in the development of allergic inflammation, subsequent studies showed that this is true only at relatively low doses of LPS. A high dose of LPS was shown to actually suppress eosinophilic airway inflammation. In our efforts to understand the mechanism underlying LPS-mediated suppression of allergic airway disease, we recently showed that LPS induces MDSC-like cells in the lung tissue in a dose-dependent manner, with increased accumulation of the cells at high doses of LPS. In contrast to lung dendritic cells (DCs), the MDSC-like cells did not traffic to the lung-draining lymph nodes, allowing them to act in a dominant fashion over DCs in the regulation of Th2 responses. The MDSC-like cells were found to blunt the ability of the lung DCs to upregulate GATA-3 or to promote STAT5 activation in primed Th2 cells, both transcription factors having critical roles in Th2 effector function. Thus, a complete understanding of the generation and regulation of the lung MDSCs would provide novel options for therapeutic interventions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Frey AB. Myeloid suppressor cells regulate the adaptive immune response to cancer. J Clin Invest. 2006;116:2587–90.

    Article  PubMed  CAS  Google Scholar 

  2. Dolcetti L, Marigo I, Mantelli B, Peranzoni E, Zanovello P, Bronte V. Myeloid-derived suppressor cell role in tumor-related inflammation. Cancer Lett. 2008;267:216–25.

    Article  PubMed  CAS  Google Scholar 

  3. Coombes JL, Siddiqui KR, Arancibia-Carcamo CV, Hall J, Sun CM, Belkaid Y, et al. A functionally specialized population of mucosal CD103+DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J Exp Med. 2007;204:1757–64.

    Article  PubMed  CAS  Google Scholar 

  4. Denning TL, Wang YC, Patel SR, Williams IR, Pulendran B. Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses. Nat Immunol. 2007;8:1086–94.

    Article  PubMed  CAS  Google Scholar 

  5. Zhu B, Bando Y, Xiao S, Yang K, Anderson AC, Kuchroo VK, et al. CD11b+Ly-6C(hi) suppressive monocytes in experimental autoimmune encephalomyelitis. J Immunol. 2007;179:5228–37.

    PubMed  CAS  Google Scholar 

  6. McCurry KR, Colvin BL, Zahorchak AF, Thomson AW. Regulatory dendritic cell therapy in organ transplantation. Transpl Int. 2006;19:525–38.

    Article  PubMed  Google Scholar 

  7. Marhaba R, Vitacolonna M, Hildebrand D, Baniyash M, Freyschmidt-Paul P, Zoller M. The importance of myeloid-derived suppressor cells in the regulation of autoimmune effector cells by a chronic contact eczema. J Immunol. 2007;179:5071–81.

    PubMed  CAS  Google Scholar 

  8. Michel O, Nagy AM, Schroeven M, Duchateau J, Neve J, Fondu P, et al. Dose-response relationship to inhaled endotoxin in normal subjects. Am J Respir Crit Care Med. 1997;156:1157–64.

    PubMed  CAS  Google Scholar 

  9. Braun-Fahrlander C, Riedler J, Herz U, Eder W, Waser M, Grize L, et al. Environmental exposure to endotoxin and its relation to asthma in school-age children. N Engl J Med. 2002;347:869–77.

    Article  PubMed  Google Scholar 

  10. Radon K, Ehrenstein V, Praml G, Nowak D. Childhood visits to animal buildings and atopic diseases in adulthood: an age-dependent relationship. Am J Ind Med. 2004;46:349–56.

    Article  PubMed  Google Scholar 

  11. Horak F Jr, Studnicka M, Gartner C, Veiter A, Tauber E, Urbanek R, et al. Parental farming protects children against atopy: longitudinal evidence involving skin prick tests. Clin Exp Allergy. 2002;32:1155–9.

    Article  PubMed  Google Scholar 

  12. Prior C, Falk M, Frank A. Longitudinal changes of sensitization to farming-related antigens among young farmers. Respiration. 2001;68:46–50.

    Article  PubMed  CAS  Google Scholar 

  13. Eisenbarth SC, Piggott DA, Huleatt JW, Visintin I, Herrick CA, Bottomly K. Lipopolysaccharide-enhanced, toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen. J Exp Med. 2002;196:1645–51.

    Article  PubMed  CAS  Google Scholar 

  14. Gerhold K, Blumchen K, Bock A, Seib C, Stock P, Kallinich T, et al. Endotoxins prevent murine IgE production, T(H)2 immune responses, and development of airway eosinophilia but not airway hyperreactivity. J Allergy Clin Immunol. 2002;110:110–6.

    Article  PubMed  CAS  Google Scholar 

  15. Rodriguez D, Keller AC, Faquim-Mauro EL, de Macedo MS, Cunha FQ, Lefort J, et al. Bacterial lipopolysaccharide signaling through toll-like receptor 4 suppresses asthma-like responses via nitric oxide synthase 2 activity. J Immunol. 2003;171:1001–8.

    PubMed  CAS  Google Scholar 

  16. Delayre-Orthez C, Becker J, de Blay F, Frossard N, Pons F. Exposure to endotoxins during sensitization prevents further endotoxin-induced exacerbation of airway inflammation in a mouse model of allergic asthma. Int Arch Allergy Immunol. 2005;138:298–304.

    Article  PubMed  CAS  Google Scholar 

  17. Arora M, Poe SL, Oriss TB, Krishnamoorthy N, Yarlagadda M, Wenzel SE, et al. TLR4/MyD88-induced CD11b+Gr-1 int F4/80+ non-migratory myeloid cells suppress Th2 effector function in the lung. Mucosal Immunol. 2010;3:578–93.

    Article  PubMed  CAS  Google Scholar 

  18. Yazdanbakhsh M, Kremsner PG, van Ree R. Allergy, parasites, and the hygiene hypothesis. Science (New York, NY). 2002;296:490–4.

  19. Caramalho I, Lopes-Carvalho T, Ostler D, Zelenay S, Haury M, Demengeot J. Regulatory T cells selectively express toll-like receptors and are activated by lipopolysaccharide. J Exp Med. 2003;197:403–11.

    Article  PubMed  CAS  Google Scholar 

  20. Tulic MK, Manoukian JJ, Eidelman DH, Hamid Q. T-cell proliferation induced by local application of LPS in the nasal mucosa of nonatopic children. J Allergy Clin Immunol. 2002;110:771–6.

    Article  PubMed  CAS  Google Scholar 

  21. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009;9:162–74.

    Article  PubMed  CAS  Google Scholar 

  22. Youn JI, Nagaraj S, Collazo M, Gabrilovich DI. Subsets of myeloid-derived suppressor cells in tumor-bearing mice. J Immunol. 2008;181:5791–802.

    PubMed  CAS  Google Scholar 

  23. Makarenkova VP, Bansal V, Matta BM, Perez LA, Ochoa JB. CD11b+/Gr-1+ myeloid suppressor cells cause T cell dysfunction after traumatic stress. J Immunol. 2006;176:2085–94.

    PubMed  CAS  Google Scholar 

  24. Condamine T, Gabrilovich DI. Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and function. Trends Immunol. 2011;32:19–25.

    Article  PubMed  CAS  Google Scholar 

  25. Pan PY, Wang GX, Yin B, Ozao J, Ku T, Divino CM, et al. Reversion of immune tolerance in advanced malignancy: modulation of myeloid-derived suppressor cell development by blockade of stem-cell factor function. Blood. 2008;111:219–28.

    Article  PubMed  CAS  Google Scholar 

  26. Sinha P, Clements VK, Fulton AM, Ostrand-Rosenberg S. Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells. Cancer Res. 2007;67:4507–13.

    Article  PubMed  CAS  Google Scholar 

  27. Cheng P, Corzo CA, Luetteke N, Yu B, Nagaraj S, Bui MM, et al. Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein. J Exp Med. 2008;205:2235–49.

    Article  PubMed  CAS  Google Scholar 

  28. Gabrilovich D, Ishida T, Oyama T, Ran S, Kravtsov V, Nadaf S, et al. Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood. 1998;92:4150–66.

    PubMed  CAS  Google Scholar 

  29. Liu YY, Sun LC, Wei JJ, Li D, Yuan Y, Yan B, et al. Tumor cell-released TLR4 ligands stimulate Gr-1+CD11b+F4/80+ cells to induce apoptosis of activated T cells. J Immunol. 2010;185:2773–82.

    Article  PubMed  CAS  Google Scholar 

  30. Lechner MG, Liebertz DJ, Epstein AL. Characterization of cytokine-induced myeloid-derived suppressor cells from normal human peripheral blood mononuclear cells. J Immunol. 2010;185:2273–84.

    Article  PubMed  CAS  Google Scholar 

  31. Massberg S, Schaerli P, Knezevic-Maramica I, Kollnberger M, Tubo N, Moseman EA, et al. Immunosurveillance by hematopoietic progenitor cells trafficking through blood, lymph, and peripheral tissues. Cell. 2007;131:994–1008.

    Article  PubMed  CAS  Google Scholar 

  32. Delano MJ, Scumpia PO, Weinstein JS, Coco D, Nagaraj S, Kelly-Scumpia KM, et al. MyD88-dependent expansion of an immature GR-1(+)CD11b(+) population induces T cell suppression and Th2 polarization in sepsis. J Exp Med. 2007;204:1463–74.

    Article  PubMed  CAS  Google Scholar 

  33. De Wilde V, Van Rompaey N, Hill M, Lebrun JF, Lemaitre P, Lhomme F, et al. Endotoxin-induced myeloid-derived suppressor cells inhibit alloimmune responses via heme oxygenase-1. Am J Transpl. 2009;9:2034–47.

    Article  Google Scholar 

  34. Vaknin I, Blinder L, Wang L, Gazit R, Shapira E, Genina O, et al. A common pathway mediated through toll-like receptors leads to T- and natural killer-cell immunosuppression. Blood. 2008;111:1437–47.

    Article  PubMed  CAS  Google Scholar 

  35. Rossner S, Voigtlander C, Wiethe C, Hanig J, Seifarth C, Lutz MB. Myeloid dendritic cell precursors generated from bone marrow suppress T cell responses via cell contact and nitric oxide production in vitro. Eur J Immunol. 2005;35:3533–44.

    Article  PubMed  Google Scholar 

  36. Bartz H, Avalos NM, Baetz A, Heeg K, Dalpke AH. Involvement of suppressors of cytokine signaling in toll-like receptor-mediated block of dendritic cell differentiation. Blood. 2006;108:4102–8.

    Article  PubMed  CAS  Google Scholar 

  37. Nefedova Y, Huang M, Kusmartsev S, Bhattacharya R, Cheng P, Salup R, et al. Hyperactivation of STAT3 is involved in abnormal differentiation of dendritic cells in cancer. J Immunol. 2004;172:464–74.

    PubMed  CAS  Google Scholar 

  38. Zhang M, Liu Q, Mi S, Liang X, Zhang Z, Su X, et al. Both miR-17-5p and miR-20a alleviate suppressive potential of myeloid-derived suppressor cells by modulating STAT3 expression. J Immunol. 2011;186:4716–24.

    Article  PubMed  CAS  Google Scholar 

  39. Zheng W, Flavell RA. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell. 1997;89:587–96.

    Article  PubMed  CAS  Google Scholar 

  40. Zhang DH, Cohn L, Ray P, Bottomly K, Ray A. Transcription factor GATA-3 is differentially expressed in murine Th1 and Th2 cells and controls Th2-specific expression of the interleukin-5 gene. J Biol Chem. 1997;272:21597–603.

    Article  PubMed  CAS  Google Scholar 

  41. Zhu J, Cote-Sierra J, Guo L, Paul WE. Stat5 activation plays a critical role in Th2 differentiation. Immunity. 2003;19:739–48.

    Article  PubMed  CAS  Google Scholar 

  42. Hand TW, Cui W, Jung YW, Sefik E, Joshi NS, Chandele A, et al. Differential effects of STAT5 and PI3 K/AKT signaling on effector and memory CD8 T-cell survival. Proc Natl Acad Sci USA. 2010;107:16601–6.

    Article  PubMed  CAS  Google Scholar 

  43. Wofford JA, Wieman HL, Jacobs SR, Zhao Y, Rathmell JC. IL-7 promotes Glut1 trafficking and glucose uptake via STAT5-mediated activation of Akt to support T-cell survival. Blood. 2008;111:2101–11.

    Article  PubMed  CAS  Google Scholar 

  44. Hu H, Huston G, Duso D, Lepak N, Roman E, Swain SL. CD4(+) T cell effectors can become memory cells with high efficiency and without further division. Nat Immunol. 2001;2:705–10.

    Article  PubMed  CAS  Google Scholar 

  45. Kusmartsev SA, Li Y, Chen SH. Gr-1+ myeloid cells derived from tumor-bearing mice inhibit primary T cell activation induced through CD3/CD28 costimulation. J Immunol. 2000;165:779–85.

    PubMed  CAS  Google Scholar 

  46. Mazzoni A, Bronte V, Visintin A, Spitzer JH, Apolloni E, Serafini P, et al. Myeloid suppressor lines inhibit T cell responses by an NO-dependent mechanism. J Immunol. 2002;168:689–95.

    PubMed  CAS  Google Scholar 

  47. Bronte V, Serafini P, De Santo C, Marigo I, Tosello V, Mazzoni A, et al. IL-4-induced arginase 1 suppresses alloreactive T cells in tumor-bearing mice. J Immunol. 2003;170:270–8.

    PubMed  CAS  Google Scholar 

  48. Bronte V, Serafini P, Mazzoni A, Segal DM, Zanovello P. l-arginine metabolism in myeloid cells controls T-lymphocyte functions. Trends Immunol. 2003;24:302–6.

    Article  PubMed  CAS  Google Scholar 

  49. Kusmartsev S, Nefedova Y, Yoder D, Gabrilovich DI. Antigen-specific inhibition of CD8+ T cell response by immature myeloid cells in cancer is mediated by reactive oxygen species. J Immunol. 2004;172:989–99.

    PubMed  CAS  Google Scholar 

  50. Srivastava MK, Sinha P, Clements VK, Rodriguez P, Ostrand-Rosenberg S. Myeloid-derived suppressor cells inhibit T-cell activation by depleting cystine and cysteine. Cancer Res. 2010;70:68–77.

    Article  PubMed  CAS  Google Scholar 

  51. Rodriguez PC, Hernandez CP, Quiceno D, Dubinett SM, Zabaleta J, Ochoa JB, et al. Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma. J Exp Med. 2005;202:931–9.

    Article  PubMed  CAS  Google Scholar 

  52. Yang L, Huang J, Ren X, Gorska AE, Chytil A, Aakre M, et al. Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. Cancer Cell. 2008;13:23–35.

    Article  PubMed  CAS  Google Scholar 

  53. Huang B, Pan PY, Li Q, Sato AI, Levy DE, Bromberg J, et al. Gr-1+CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host. Cancer Res. 2006;66:1123–31.

    Article  PubMed  CAS  Google Scholar 

  54. Serafini P, Mgebroff S, Noonan K, Borrello I. Myeloid-derived suppressor cells promote cross-tolerance in B-cell lymphoma by expanding regulatory T cells. Cancer Res. 2008;68:5439–49.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by US National Institutes of Health grants HL 060207 and HL 069810 (to PR), HL 077430 and AI 048927 (to AR), HL 084932 (to PR and AR), a grant from the American Heart Association, AHA 0865379D (to MA), and T32 HL007563 (to S.S. that funded SP).

Conflict of interest

The authors declare no conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, 3459 Fifth Avenue, MUH A628 NW, Pittsburgh, PA, 15213, USA

    Prabir Ray, Meenakshi Arora, Stephanie L. Poe & Anuradha Ray

  2. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA

    Prabir Ray, Stephanie L. Poe & Anuradha Ray

Authors
  1. Prabir Ray
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Meenakshi Arora
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stephanie L. Poe
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anuradha Ray
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Prabir Ray.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ray, P., Arora, M., Poe, S.L. et al. Lung myeloid-derived suppressor cells and regulation of inflammation. Immunol Res 50, 153–158 (2011). https://doi.org/10.1007/s12026-011-8230-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12026-011-8230-1

Keywords

Search

Navigation