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Transplantation. Author manuscript; available in PMC 2009 Oct 27.
Center for Molecular Chaperone/Radiobiology and Cancer Virology, Department of Medicine, Medical College of Georgia, 1410 Laney Walker Blvd, Augusta, GA 30912-2615
Corresponding author: Anatolij Horuzsko, M.D., Ph.D., Center for Molecular Chaperone/Radiobiology and Cancer Virology, Department of Medicine, Medical College of Georgia, 1410 Laney Walker Blvd, Augusta, GA 30912-2615. Phone: 1-706-721-8736. Fax: 1-706-721-0101. E-mail: ude.gcm@okszuroha
Current address for all authors: Center for Molecular Chaperone/Radiobiology and Cancer Virology, Medical College of Georgia, 1410 Laney Walker Blvd, Augusta, GA 30912-2615
The publisher's final edited version of this article is available at Transplantation
GUID: 924E4C1B-778E-491C-BF82-235785205027
Keywords: Immunosuppression, Myeloid-derived suppressor cells, HLA-G, Inhibitory receptor, Allograft survival, Mice
a The average fold changes were obtained by comparison of nonactivated MDSCs isolated from splenocytes of ILT2 mice with MDSCs isolated from splenocytes of control C57BL/6 mice.
b Fold changes in allogeneic transplant-activated MDSCs from ILT2 mice compared with allogeneic transplant-activated MDSCs from C57BL/6 mice indicated in bracket.
1. Carosella ED, Moreau P, Le Maoult J, Le Discorde M, Dausset J, Rouas-Freiss N. HLA-G molecules: from maternal-fetal tolerance to tissue acceptance. Adv Immunol. 2003; 81 :199. [ PubMed ] [ Google Scholar ]
2. Rouas-Freiss N, LeMaoult J, Moreau P, Dausset J, Carosella ED. HLA-G in transplantation: a relevant molecule for inhibition of graft rejection? Am J Transplant. 2003; 3 :11. [ PubMed ] [ Google Scholar ]
3. Hunt JS, Petroff MG, McIntire RH, Ober C. HLA-G and immune tolerance in pregnancy. Faseb J. 2005; 19 :681. [ PubMed ] [ Google Scholar ]
4. Carosella ED, Moreau P, Lemaoult J, Rouas-Freiss N. HLA-G: from biology to clinical benefits. Trends Immunol. 2008; 29 :125. [ PubMed ] [ Google Scholar ]
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12. Liang S, Ristich V, Arase H, Dausset J, Carosella ED, Horuzsko A. Modulation of dendritic cell differentiation by HLA-G and ILT4 requires the IL-6-STAT3 signaling pathway. Proc Natl Acad Sci U S A. 2008; 105 :8357. [ PMC free article ] [ PubMed ] [ Google Scholar ]
13. Feger U, Tolosa E, Huang YH, et al. HLA-G expression defines a novel regulatory T-cell subset present in human peripheral blood and sites of inflammation. Blood. 2007; 110 :568. [ PubMed ] [ Google Scholar ]
14. Rouas-Freiss N, Naji A, Durrbach A, Carosella ED. Tolerogenic functions of human leukocyte antigen G: from pregnancy to organ and cell transplantation. Transplantation. 2007; 84 (1 Suppl):S21. [ PubMed ] [ Google Scholar ]
15. Gallina G, Dolcetti L, Serafini P, et al. Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells. J Clin Invest. 2006; 116 :2777. [ PMC free article ] [ PubMed ] [ Google Scholar ]
16. Yang L, DeBusk LM, Fukuda K, et al. Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell. 2004; 6 :409. [ PubMed ] [ Google Scholar ]
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19. Nagaraj S, Gupta K, Pisarev V, et al. Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer. Nat Med. 2007; 13 :828. [ PMC free article ] [ PubMed ] [ Google Scholar ]
20. Liang S, Baibakov B, Horuzsko A. HLA-G inhibits the functions of murine dendritic cells via the PIR-B immune inhibitory receptor. Eur J Immunol. 2002; 32 :2418. [ PubMed ] [ Google Scholar ]
21. Ochoa JB, Bernard AC, O'Brien WE, et al. Arginase I expression and activity in human mononuclear cells after injury. Ann Surg. 2001; 233 :393. [ PMC free article ] [ PubMed ] [ Google Scholar ]
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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. [ PubMed ] [ Google Scholar ]
24. Broxmeyer HE, Cooper S, Hangoc G, Chang CH. Class II transactivator-mediated regulation of major histocompatibility complex class II antigen expression is important for hematopoietic progenitor cell suppression by chemokines and iron-binding proteins. Exp Hematol. 2006; 34 :1078. [ PubMed ] [ Google Scholar ]
25. Bunt SK, Sinha P, Clements VK, Leips J, Ostrand-Rosenberg S. Inflammation induces myeloid-derived suppressor cells that facilitate tumor progression. J Immunol. 2006; 176 :284. [ PubMed ] [ Google Scholar ]
26. Zheng XX, Sanchez-Fueyo A, Domenig C, Strom TB. The balance of deletion and regulation in allograft tolerance. Immunol Rev. 2003; 196 :75. [ PubMed ] [ Google Scholar ]
27. Wood KJ, Sakaguchi S. Regulatory T cells in transplantation tolerance. Nat Rev Immunol. 2003; 3 :199. [ PubMed ] [ Google Scholar ]
28. Wells AD, Li XC, Strom TB, Turka LA. The role of peripheral T-cell deletion in transplantation tolerance. Philos Trans R Soc Lond B Biol Sci. 2001; 356 :617. [ PMC free article ] [ PubMed ] [ Google Scholar ]
29. Wood KJ, Jones ND, Bushell AR, Morris PJ. Alloantigen-induced specific immunological unresponsiveness. Philos Trans R Soc Lond B Biol Sci. 2001; 356 :665. [ PMC free article ] [ PubMed ] [ Google Scholar ]
30. Waldmann H, Cobbold S. Regulating the immune response to transplants. a role for CD4+ regulatory cells? Immunity. 2001; 14 :399. [ PubMed ] [ Google Scholar ]
31. Graca L, Cobbold SP, Waldmann H. Identification of regulatory T cells in tolerated allografts. J Exp Med. 2002; 195 :1641. [ PMC free article ] [ PubMed ] [ Google Scholar ]
32. Bach JF. Regulatory T cells under scrutiny. Nat Rev Immunol. 2003; 3 :189. [ PubMed ] [ Google Scholar ]
33. Dietrich J, Cella M, Colonna M. Ig-like transcript 2 (ILT2)/leukocyte Ig-like receptor 1 (LIR1) inhibits TCR signaling and actin cytoskeleton reorganization. J Immunol. 2001; 166 :2514. [ PubMed ] [ Google Scholar ]
34. Sayos J, Martinez-Barriocanal A, Kitzig F, Bellon T, Lopez-Botet M. Recruitment of C-terminal Src kinase by the leukocyte inhibitory receptor CD85j. Biochem Biophys Res Commun. 2004; 324 :640. [ PubMed ] [ Google Scholar ]
35. Lowell CA. Src-family kinases: rheostats of immune cell signaling. Mol Immunol. 2004; 41 :631. [ PubMed ] [ Google Scholar ]
36. Karur VG, Lowell CA, Besmer P, Agosti V, Wojchowski DM. Lyn kinase promotes erythroblast expansion and late-stage development. Blood. 2006; 108 :1524. [ PMC free article ] [ PubMed ] [ Google Scholar ]
37. 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. [ PubMed ] [ Google Scholar ]
38. Frey AB. Myeloid suppressor cells regulate the adaptive immune response to cancer. J Clin Invest. 2006; 116 :2587. [ PMC free article ] [ PubMed ] [ Google Scholar ]
1. Carosella ED, Moreau P, Le Maoult J, Le Discorde M, Dausset J, Rouas-Freiss N. HLA-G molecules: from maternal-fetal tolerance to tissue acceptance. Adv Immunol. 2003; 81 :199. [ PubMed ] [ Google Scholar ] [ Ref list ]
4. Carosella ED, Moreau P, Lemaoult J, Rouas-Freiss N. HLA-G: from biology to clinical benefits. Trends Immunol. 2008; 29 :125. [ PubMed ] [ Google Scholar ] [ Ref list ]
5. Hunt JS, Jadhav L, Chu W, Geraghty DE, Ober C. Soluble HLA-G circulates in maternal blood during pregnancy. Am J Obstet Gynecol. 2000; 183 :682. [ PubMed ] [ Google Scholar ] [ Ref list ]
12. Liang S, Ristich V, Arase H, Dausset J, Carosella ED, Horuzsko A. Modulation of dendritic cell differentiation by HLA-G and ILT4 requires the IL-6-STAT3 signaling pathway. Proc Natl Acad Sci U S A. 2008; 105 :8357. [ PMC free article ] [ PubMed ] [ Google Scholar ] [ Ref list ]
11. Liang S, Zhang W, Horuzsko A. Human ILT2 receptor associates with murine MHC class I molecules in vivo and impairs T cell function. Eur J Immunol. 2006; 36 :2457. [ PubMed ] [ Google Scholar ] [ Ref list ]
13. Feger U, Tolosa E, Huang YH, et al. HLA-G expression defines a novel regulatory T-cell subset present in human peripheral blood and sites of inflammation. Blood. 2007; 110 :568. [ PubMed ] [ Google Scholar ] [ Ref list ]
14. Rouas-Freiss N, Naji A, Durrbach A, Carosella ED. Tolerogenic functions of human leukocyte antigen G: from pregnancy to organ and cell transplantation. Transplantation. 2007; 84 (1 Suppl):S21. [ PubMed ] [ Google Scholar ] [ Ref list ]
15. Gallina G, Dolcetti L, Serafini P, et al. Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells. J Clin Invest. 2006; 116 :2777. [ PMC free article ] [ PubMed ] [ Google Scholar ] [ Ref list ]
19. Nagaraj S, Gupta K, Pisarev V, et al. Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer. Nat Med. 2007; 13 :828. [ PMC free article ] [ PubMed ] [ Google Scholar ] [ Ref list ]
20. Liang S, Baibakov B, Horuzsko A. HLA-G inhibits the functions of murine dendritic cells via the PIR-B immune inhibitory receptor. Eur J Immunol. 2002; 32 :2418. [ PubMed ] [ Google Scholar ] [ Ref list ]
21. Ochoa JB, Bernard AC, O'Brien WE, et al. Arginase I expression and activity in human mononuclear cells after injury. Ann Surg. 2001; 233 :393. [ PMC free article ] [ PubMed ] [ Google Scholar ] [ Ref list ]
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. [ PubMed ] [ Google Scholar ] [ Ref list ]
24. Broxmeyer HE, Cooper S, Hangoc G, Chang CH. Class II transactivator-mediated regulation of major histocompatibility complex class II antigen expression is important for hematopoietic progenitor cell suppression by chemokines and iron-binding proteins. Exp Hematol. 2006; 34 :1078. [ PubMed ] [ Google Scholar ] [ Ref list ]
25. Bunt SK, Sinha P, Clements VK, Leips J, Ostrand-Rosenberg S. Inflammation induces myeloid-derived suppressor cells that facilitate tumor progression. J Immunol. 2006; 176 :284. [ PubMed ] [ Google Scholar ] [ Ref list ]
26. Zheng XX, Sanchez-Fueyo A, Domenig C, Strom TB. The balance of deletion and regulation in allograft tolerance. Immunol Rev. 2003; 196 :75. [ PubMed ] [ Google Scholar ] [ Ref list ]
27. Wood KJ, Sakaguchi S. Regulatory T cells in transplantation tolerance. Nat Rev Immunol. 2003; 3 :199. [ PubMed ] [ Google Scholar ] [ Ref list ]
29. Wood KJ, Jones ND, Bushell AR, Morris PJ. Alloantigen-induced specific immunological unresponsiveness. Philos Trans R Soc Lond B Biol Sci. 2001; 356 :665. [ PMC free article ] [ PubMed ] [ Google Scholar ] [ Ref list ]
30. Waldmann H, Cobbold S. Regulating the immune response to transplants. a role for CD4+ regulatory cells? Immunity. 2001; 14 :399. [ PubMed ] [ Google Scholar ] [ Ref list ]
32. Bach JF. Regulatory T cells under scrutiny. Nat Rev Immunol. 2003; 3 :189. [ PubMed ] [ Google Scholar ] [ Ref list ]
33. Dietrich J, Cella M, Colonna M. Ig-like transcript 2 (ILT2)/leukocyte Ig-like receptor 1 (LIR1) inhibits TCR signaling and actin cytoskeleton reorganization. J Immunol. 2001; 166 :2514. [ PubMed ] [ Google Scholar ] [ Ref list ]
34. Sayos J, Martinez-Barriocanal A, Kitzig F, Bellon T, Lopez-Botet M. Recruitment of C-terminal Src kinase by the leukocyte inhibitory receptor CD85j. Biochem Biophys Res Commun. 2004; 324 :640. [ PubMed ] [ Google Scholar ] [ Ref list ]
35. Lowell CA. Src-family kinases: rheostats of immune cell signaling. Mol Immunol. 2004; 41 :631. [ PubMed ] [ Google Scholar ] [ Ref list ]
36. Karur VG, Lowell CA, Besmer P, Agosti V, Wojchowski DM. Lyn kinase promotes erythroblast expansion and late-stage development. Blood. 2006; 108 :1524. [ PMC free article ] [ PubMed ] [ Google Scholar ] [ Ref list ]
16. Yang L, DeBusk LM, Fukuda K, et al. Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell. 2004; 6 :409. [ PubMed ] [ Google Scholar ] [ Ref list ]
18. Serafini P, Borrello I, Bronte V. Myeloid suppressor cells in cancer: recruitment, phenotype, properties, and mechanisms of immune suppression. Semin Cancer Biol. 2006; 16 :53. [ PubMed ] [ Google Scholar ] [ Ref list ]
37. 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. [ PubMed ] [ Google Scholar ] [ Ref list ]
38. Frey AB. Myeloid suppressor cells regulate the adaptive immune response to cancer. J Clin Invest. 2006; 116 :2587. [ PMC free article ] [ PubMed ] [ Google Scholar ] [ Ref list ]
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The expression of HLA-G during allogeneic recognition is associated with better graft acceptance. The inhibitory receptor ILT2 is expressed on activated T cells and serves to shut down T cell activation, culminating in T cell death or induction of anergy. One of the potential mechanisms in the immunosuppressive accomplishment of HLA-G-ILT2 interactions involves the expansion of myeloid-derived suppressor cells (MDSCs). The potential of MDSCs in transplantation has not yet been exploited.
(1) Detailed phenotypic characteristics, immunosuppressive potential of MDSCs expanded via inhibitory receptor ILT2 and its ligands, and allogeneic transplant-activated MDSCs were obtained in mice. (2) Oligo- and Real-time pathway-specific PCR Arrays were performed to characterize ILT2-specific MDSCs. (3) Skin allograft survival after adoptive transfer of MDSCs was studied.
Engagement of ILT2 receptors, especially by HLA-G, expanded the population of MDSCs with enhanced suppressive activity. Adoptive transfer of MDSCs generated via ILT2 receptor and its ligands prolonged graft survival in recipients of allogeneic skin transplant. We have proposed pathways for enhancement of immunosuppressive activities and expansion of MDSCs via ILT2 and HLA-G.
Our results suggest that induction of MDSCs using ILT2 inhibitory receptor/HLA-G ligand may be an attractive strategy for preventing rejection of highly immunogenic organs/tissues in clinical transplantation.
The induction of immune tolerance continues to be an important goal of clinical organ and tissue transplantation. The immunological acceptance of a fetal semiallograft during pregnancy is a natural model of immune tolerance, and its underlying mechanisms can be exploited to prevent allograft rejection in clinical transplantation. One of the potential mechanisms involves HLA-G, a human immunosuppressive non-classical MHC molecule ( 1 – 4 ). Evidence suggests that HLA-G protects the fetus from attack by natural killer cells, macrophages, dendritic cells (DCs), monocytes, and T cells by interacting with immune inhibitory receptors, such as immunoglobulin-like transcript 2 (ILT2) and ILT4, and modifying cell functions ( 5 – 12 ). The unique characteristics of both cell-surface and soluble isoforms of HLA-G, the formation of disulfide-bonded dimers with the potential to augment inhibitory receptor signaling, the function of HLA-G as a preferential ligand for the ILTs, and its presence in patients with kidney, kidney/liver, and heart allografts, make HLA-G very important in fundamental approaches for modulation of immune responses to improve allogeneic graft survival in clinical transplantation.
ILT2, also known as LILRB1, LIR-1, and CD85j, is an inhibitory receptor broadly expressed on human T and B lymphocytes and on antigen presenting cells, modulating their functions. Mechanisms of the modulation of immune responses by HLA-G and ILT2 include generation and/or expansion of cell populations that negatively regulate T cell functions ( 11 , 13 , 14 ). One example of these powerful natural regulato
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