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LIF in the regulation of T-cell fate and as a potential therapeutic

Genes & Immunity volume 12, pages 157–168 (2011)Cite this article

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Abstract

At the heart of lineage commitment within the adaptive immune response is the intrinsic genetic plasticity of the naive peripheral T lymphocyte (T cell). Primary activation by presentation of cognate antigen is coupled to rapid T-cell cycling and progressive epigenetic changes that guide the cell down distinct T-cell lineages, either effector (Th1, Th2, Th17) or tolerogenic (Treg). Fate choice is influenced both by strength of the priming activation signal and by cues from the micro-environment that are integrated with lineage-specific gene expression profiles, eventually becoming hard-wired in the fully differentiated cell. The micro-environmental cues include cytokines, and the discovery that leukaemia inhibitory factor (LIF) and interleukin (IL)-6 counter-regulate development of the Treg and Th17 lineages places LIF within the core regulatory circuitry of T cells. I first summarise current understanding of LIF and the LIF receptor in the context of T cells. Next, the central relevance of the LIF/IL-6 axis in immune-mediated disease is set in the context of (i) a new nano-therapeutic approach for targeted delivery of LIF and (ii) MARCH-7, a novel E3-ligase discovered to have a central mechanistic role in LIF-mediated T-cell biology, functioning as a rheostat-type regulator of endogenous LIF-signalling.

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References

  1. Metcalfe SM, De S Muthukumarana PA . Transplantation tolerance: gene expression profiles comparing allotolerance vs allorejection. Int Immunopharmacol 2005; 5: 33–39.

    Article  CAS  PubMed  Google Scholar 

  2. Metcalfe SM, Watson TJ, Shurey S, Adams E, Green CJ . Leukaemia inhibitory factor (LIF) is linked to regulatory transplantation tolerance. Transplantation 2005; 79: 726–730.

    Article  CAS  PubMed  Google Scholar 

  3. Metcalf D . Unsolved enigmas of leukaemia inhibitory factor. Stem Cells 2003; 21: 5–14.

    Article  CAS  PubMed  Google Scholar 

  4. Auernhammer CJ, Melmed S . Leukaemia inhibitory factor—neuroimmune modulator of endocrine function. Endocrine Rev 2000; 21: 313–345.

    CAS  Google Scholar 

  5. Langlais D, Couture C, Balsalobre A, Drouin J . Regulatory network analyses reveal genome-wide potentiation of LIF signaling by glucocorticoids and define an innate cell defence response. PLoS Genet 2008; 4: e1000224.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Bauer S, Kerr BJ, Patterson PH . The neuropoietic cytokine family in development, plasticity, disease and injury. Nat Rev Neurosci 2007; 8: 221–232.

    Article  CAS  PubMed  Google Scholar 

  7. Niwa H, Ogawa K, Shimosato D, Adachi K . A parallel circuit of LIF signalling pathways maintains pluripotency of mouse ES cells. Nature 2009; 460: 118–122.

    Article  CAS  PubMed  Google Scholar 

  8. Silva J, Smith A . Capturing pluripotency. Cell 2008; 132: 532–536.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Chambers I, Silva J, Colby D, Nichols J, Robertson M, Nijmeijer B et al. Nanog safeguards pluripotency and mediates germ cell development. Nature 2007; 450: 1230–1234.

    Article  CAS  PubMed  Google Scholar 

  10. Silva J, Nichols J, Theunissen TW, Guo G, Oosten ALV, Barrandon O et al. Nanog is the gateway to the pluripotent ground state. Cell 2009; 138: 722–737.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zhang P, Andrianakos R, Yang Y, Liu C, Lu W . Kruppel-like factor 4 (KLF4) prevents embryonic stem (ES) cell differentiation by regulating Nanog gene expression. J Biol Chem 2010; 285: 9180–9189.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hall J, Guo G, Wray J, Eyres I, Nichols J, Grotewold L et al. Oct4 and LIF/Stat3 additively induce Kruppel factors to sustain embryonic stem cell self-renewal. Cell Stem Cell 2009; 5: 597–609.

    Article  CAS  PubMed  Google Scholar 

  13. Alberti K, Davey RE, Onishi K, George S, Salchert K, Seib FP et al. Functional immobilization of signaling proteins enables control of stem cell fate. Nat Methods 2008; 5: 645–650.

    Article  CAS  PubMed  Google Scholar 

  14. Takahashi K, Yamanaka S . Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006; 126: 663–676.

    Article  CAS  PubMed  Google Scholar 

  15. Pereira CF, Terranova R, Ryan NK, Santos J, Morris KJ, Cui W et al. Heterokaryon-based reprogramming of human b lymphocytes for pluripotency requires Oct4 but Not Sox2. PLoS Genet 2008; 4: 1–14.

    Article  CAS  Google Scholar 

  16. Thompson HL, Whiston RA, Rakhimov Y, Taccioli C, Liu CG, Croce C et al. A LIF/Nanog axis is revealed in T lymphocytes that lack MARCH-7, a RINGv E3 ligase that regulates the LIF-receptor. Cell Cycle 2010; 9: 4213–4221.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Chemicon International. LIF.

  18. Ibelgauft H . LIF in cytokines & cells online pathfinder encylopedia. COPE 2010 version 24.7.

  19. Shen MM, Skoda RC, Cardiff RD, Campos-Torres J, Leder P, Ornitz DM . Expression of LIF in transgenic mice results in altered thymic epithelium and apparent interconversion of thymic and lymph node morphologies. EMBO J 1994; 13: 1375–1385.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Schluns KS, Cookk JE, Le PT . TGF-beta differentially modulates epidermal growth factor-mediated increases in leukaemia inhibitory factor, IL-6, IL-1 alpha, and IL-1 beta in human thymic epithelial cells. J Immunol 1997; 158: 2704–2712.

    CAS  PubMed  Google Scholar 

  21. Sempowski GD, Hale LP, Sunday JS, Massey JM, Koup RA, Douek DC et al. LIF, oncostatin M IL-6 and stem cell fator mRNA expression in human thymus increases with age and is associated with thymic atrophy. J immunol 2000; 164: 2180–2187.

    Article  CAS  PubMed  Google Scholar 

  22. Haynes BF . Human thymic epithelium and T cell development: current issues and future directions. Thymus 1990; 16: 143–157.

    CAS  PubMed  Google Scholar 

  23. Bamberger AM, Jenatschke S, Schulte HM, Ellebrecht I, Biel FU, Bamberger C . Regulation of the human leukemia inhibitory factor gene by ETS transcription factors. Neuroimmunomodulation 2004; 11: 10–19.

    Article  PubMed  CAS  Google Scholar 

  24. Haines BP, Voyle RB, Rathjen PD . Intracellular and extracellular leukaemia inhibitory factor proteins have different cellular activities that are mediated by distinct protein motifs. Mol Biol Cell 2000; 11: 1369–1383.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Haines BP, Voyle RB, Pelton TA, Forret R, Rathjen PD . Complex conserved organisation of the mammalian leukaemia inhibitory factor gene: regulated expression of intracellular and extracellular cytokines. J Immunol 1999; 162: 4637–4646.

    CAS  PubMed  Google Scholar 

  26. Giese B, Roderburg C, Sommerauer M, Wortmann SB, Metz S, Heinrich PC et al. Dimerization of the cytokine receptors gp130 and LIFR analysed in single cells. J Cell Sci 2005; 118: 5129–5140.

    Article  CAS  PubMed  Google Scholar 

  27. Rose-John S, Scheller J, Elson G, Jones SA . IL-6 biology is coordinate by membrane bound and soluble receptors: role in inflammation and cancer. J Leuk Biol 2006; 80: 227–236.

    Article  CAS  Google Scholar 

  28. Hammacher A, Widjenes J, Hilton DJ, Nicola NA, Simpson RJ, Layton JE . Ligand-specific utilisation of the extracellular membrane-proximal region of the gp130-related signalling receptors. Biochem J 2000; 345: 25–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hammacher A, Richardson RT, Layton JE, Smith DK, Angus LJL, Hilton DJ et al. The immunoglobulin-like module of gp130 is required for signalling by IL-6, but not by LIF. J Biol Chem 1998; 273: 22701–22707.

    Article  CAS  PubMed  Google Scholar 

  30. Man D, He W, Sze KH, Gong K, Smith DK, Zhu G et al. Solution structure of the C-terminal domain of the CTNF receptor and ligand free associations among components of the CNTF receptor complex. J Biol Chem 2003; 278: 23285–23294.

    Article  CAS  PubMed  Google Scholar 

  31. Bitard J, Daburon S, Duplomb L, Blanchard F, Vuisio P, Jaques Y et al. Mutations in the immunoglobulin-like domain of gp190, the LIF receptor, increase or decrease its affinity for LIF. J Biol Chem 2003; 278: 16253–16261.

    Article  CAS  PubMed  Google Scholar 

  32. Kallen KJ, Grotzinger J, Lelievres E, Vollmer P, Aasland D, Renne C et al. Receptor recognition sites of cytokines are organised as exchangable modules. J Biol Chem 1999; 274: 11859–11867.

    Article  CAS  PubMed  Google Scholar 

  33. Niwa H, Ogawa K, Shimosato D, Adachi K . A parallel circuit of LIF signalling pathways maintains pluripotency of mouse ES cells. Nature 2009; 460: 118–122.

    Article  CAS  PubMed  Google Scholar 

  34. Gao W, Thompson L, Zhou Q, Putheti P, Fahmy TM, Strom TB et al. Treg versus Th17 lymphocyte lineages are cross-regulated by LIF versus IL-6. Cell Cycle 2009; 8: 1444–1450.

    Article  CAS  PubMed  Google Scholar 

  35. Takahashi Y, Carpino NC, Cross JC, Torres M, Parganas E, Ihle JN . SOCS3: an essential regulator of LIF receptor signaling in trophoblast giant cell differentiation. EMBO J 2003; 22: 372–384.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Bartoe JL, Nathanson NM . Independent roles of SOCS-3 and SHP-2 in the regulation of neuronal gene expression by leukemia inhibitory factor. Brain Res Mol Brain Res 2002; 107: 109–119.

    Article  Google Scholar 

  37. Clahsen T, Lehmann U, Stross C, Hermanns HM, Volkmer-Engert R, Scheider-Mergeer J et al. The tyrosine 974 within the LIF-R-chain of the gp130/LIF-R heteromeric receptor complex mediates negative regulation of LIF signalling. Cell Signall 2005; 17: 559–569.

    Article  CAS  Google Scholar 

  38. Zeigler SF . FOXP3: of mice and men. Ann Rev Immunol 2006; 24: 209–226.

    Article  CAS  Google Scholar 

  39. Li B, Greene MI . Special regulatory T cell review: FOXP3 biochemistry in regulatory T cells—how diverse signals regulate suppression. Immunology 2008; 123: 17–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Fontenot JD, Gavin MA, Rudensky AY . Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003; 4: 330–336.

    Article  CAS  PubMed  Google Scholar 

  41. Zheng Y, Rudensky AY . Foxp3 in control of the regulatory T lineage. Nat Immunol 2007; 8: 457–462.

    Article  CAS  PubMed  Google Scholar 

  42. Feuerer M, Hill A, Mathis D, Benoist C . Foxp3+ regulatory T cells: differentiation, specification, subphenotypes. Nat Immunol 2009; 10: 689–695.

    Article  CAS  PubMed  Google Scholar 

  43. Huen J, Polasnky JK, Hamman A . Epigenetic control of FOXP3 expression: the key to a stable regulatory T-cell lineage? Nat Rev Immunol 2009; 9: 83–89.

    Article  CAS  Google Scholar 

  44. Pillemer BBL, Xu H, Oriss TB, Qi Z, Ray A . Deficient SOCS3 expression in CD4+CD25+Foxp3+ regulatory T cells and SOCS3-mediated suppression of Treg function. EJI 2007; 37: 2082–2089.

    CAS  Google Scholar 

  45. Muthukumarana P, Chae WJ, Maher S, Rosengard BR, Bothwell AL, Metcalfe SM . Regulatory transplantation tolerance and ‘stemness’: evidence that Foxp3 may play a regulatory role in SOCS-3 gene transcription. Transplantation 2007; 84: S6–S11.

    Article  CAS  PubMed  Google Scholar 

  46. Muthukumarana P . Stem cell factors, axotrophin and leukaemia inhibitory factor in immune regulation. PhD thesis 2007 University of Cambridge: UK.

    Google Scholar 

  47. Rocklin RE . Partial characteristion of leukaemia inhibitory factor by concanavalin A-stimulated human lymphocytes. J Immunol 1975; 114: 1161–1165.

    CAS  PubMed  Google Scholar 

  48. Masucci G, Szigeti R, Stevens D, Masucci MG, Petersen J, Bendtzen K et al. Production of leukocyte migration inhibitory factor (LIF) in human lymphocyte subsets exposed to polyclonal activators. Cell Immunol 1984; 85: 511–518.

    Article  CAS  PubMed  Google Scholar 

  49. Escary JL, Perreau J, Dumenil D, Ezine S, Brulet P . Leukaemia inhibitory factor is necessary for maintenance of haematopoietic stem cells and thymic simulation. Nature 1993; 363: 361–364.

    Article  CAS  PubMed  Google Scholar 

  50. Mendez-Samperio P, Jimenez-Zamudio L, Favila-Castillo L . Production of LIF and MStF by CD4+ and CD8+ human lymphocytes subsets and T cell clones. Rev Invest Clin 1989; 41: 107–115.

    CAS  PubMed  Google Scholar 

  51. Mahic M, Kalland ME, Aandahl EM, Torgersen KM, Tasken K . Human naturally occuring and adaptive regulatory T cells secrete high levels of LIF upon activation. Scand J Immunol 2008; 68: 391–396.

    Article  CAS  PubMed  Google Scholar 

  52. Fujita K, Nakayama T, Higuchi T, Fujita J, Maeda M, Fujiwara H et al. Administration of thymocytes derived from non-pregnant mice induces an endometrial receptive stage and LIF expression in the uterus. Hum Reprod 1998; 13: 2888–2894.

    Article  CAS  PubMed  Google Scholar 

  53. Hu W, Feng Z, Teresky AK, Levine AJ . p53 regulates maternal reproduction through LIF. Nature 2007; 450: 721–724.

    Article  CAS  PubMed  Google Scholar 

  54. Piccinni MP . T cells in pregnancy. Chem Immunol Allergy 2005; 89: 3–9.

    Article  CAS  PubMed  Google Scholar 

  55. Szigyarto CA, Sibbons P, Williams G, Uhlen M, Metcalfe SM . The E3 ligase ‘axotrophin/MARCH-7’: protein expression profiling of human tissues reveals links to adult stem cells. J Histochem Cytochem 2010; 58: 301–308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Human Protein Atlas. KTH www.proteinatlas.org.

  57. Zhu M, Oishi K, Lee SC, Patterson PH . Studies using LIF knockout mice and a LIF ademoviral vector demonstrate a key anti-inflammatory role for this cytokine in cutaneous inflammation. J Immunol 2001; 166: 2049–2054.

    Article  CAS  PubMed  Google Scholar 

  58. Akita S, Ishihara H, Mohammad Abdur R, Fujii T . Leukemia inhibitory factor gene improves skinallograft survival in the mouse model. Transplantation 2000; 70: 1026–1031.

    Article  CAS  PubMed  Google Scholar 

  59. Blancho G, Moreau JF, Chabannes D, Chatenoud L, Soulillou JP . HILDA/LIF, GCSF, IL-6 and TNF alpha production during acute rejection of human kidney grafts. Transplantation 1993; 56: 597–602.

    Article  CAS  PubMed  Google Scholar 

  60. Gong W, Klopfel M, Reutzel-Selke A, Jurisch A, Vogt K, Haase S et al. High weight differences between donor and recipient affect early kidney graft function—arole for enhanced IL-6 signalling. Am J Transplant 2009; 9: 1742–1751.

    Article  CAS  PubMed  Google Scholar 

  61. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006; 441: 235–238.

    Article  CAS  PubMed  Google Scholar 

  62. Nishihara M, Ogura H, Ueda N, Tsuruoka M, Kitabayashi C, Tsuji F et al. IL-6-gp130-STAT3 in T cells directs the development of IL-17+ Th with a minimum effect on that of Treg in the steady state. International Immuol 2007; 19: 659–702.

    Google Scholar 

  63. Ishihara K, Hirano T . IL-6 in autoimmune disease and chronic inflammatory proliferative disease. Cytokine Growth Factor Rev 2002; 13: 357–368.

    Article  CAS  PubMed  Google Scholar 

  64. Stasi R, Venditti A, Poeta G, Tribalto M, Coppetelli U, Zaccari G et al. High interleukin-6 plasma levels in acute promyelocytic leukemia. Annals Hematol 1992; 64: 303–304.

    Article  CAS  Google Scholar 

  65. Goodman WA, Levine AD, Massari JV, Sugiyama H, McCormick TS, Cooper KD . IL-6 signaling in psoriasis prevents immune suppression by regulatory T cells. Immunol 2009; 183: 3170–3176.

    Article  CAS  Google Scholar 

  66. Quintana A, Müller MF, Frausto RF, Ramos R, Getts DR, Sanz E et al. Site-specific production of IL- 6 in the central nervous system retargets and enhances the inflammatory response in experimental autoimmune encephalomyelitis. J Immunol 2009; 183: 2079–2088.

    Article  CAS  PubMed  Google Scholar 

  67. Muthukumarana PA, Lyons GE, Miura Y, Thompson LH, Watson T, Green CJ et al. Evidence for functional inter-relationships between FOXP3, leukaemia inhibitory factor, and axotrophin/MARCH-7 in transplantation tolerance. Int Pharmacol 2006; 6: 1993–2001.

    CAS  Google Scholar 

  68. Shen H, Goldstein DR . IL-6 and TNF- synergistically inhibit allograft acceptance. J Am Soc Nephrol 2009; 20: 1032–1040.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Park J, Gao W, Whiston R, Strom TB, Metcalfe SM, Fahmy TM . Modulation of CD4+ T lymphocyte lineage outcomes with targeted, nanoparticle-mediated cytokine delivery. Mol Pharma 2011 (in press).

  70. Reynolds AD, Stone DK, Hutter JAL, Benner EJ, Mosley RL, Gendelman HE . Regulatory T cells attenuate Th17 cell-mediated nigrostriatal dopaminergic neurodegeneration in a model of Parkinson's disease. J Immunol 2010; 184: 2261–2271.

    Article  CAS  PubMed  Google Scholar 

  71. Wild E, Bjorkqvist M, Tabrizi SJ . Immune marker's for Huntington's disease? Expert Rev Neurother 2008; 8: 1779–1781.

    Article  PubMed  Google Scholar 

  72. Björkqvist M, Wild EJ, Thiele J, Silvestroni A, Andre R, Lahiri N et al. A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington's disease. JEM 2008; 205: 1869–1877.

    Article  CAS  Google Scholar 

  73. Korn T, Reddy J, Gao W, Bettelli E, Awasthi A, Petersen TR et al. Myelin-specific regulatory T cells accumulate in the CNS but fail to control autoimmune inflammation. Nat Med 2007; 13: 423–431.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Serada S, Fujimoto M, Mihara M, Koike N, Ohsugi Y, Nomura S et al. IL-6 blockade inhibits the induction of myelin antigen-specific Th17 cells and Th1 cells in experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA 2008; 105: 9041–9046.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Chen X, Das R, Komorowski R, Beres A, Hessner MJ, Mihara M et al. Blockade of interleukin-6 signaling augments regulatory T-cell reconstitution and attenuates the severity of graft-versus-host disease. Blood 2009; 114: 891–900.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Butzkueven H, Emery B, Cipriani T, Marriott MP, Kilpatrick TJ . Endogenous leukemia inhibitory factor production limits autoimmune demyelination and oligodendrocyte loss. Glia 2006; 53: 696–703.

    Article  PubMed  Google Scholar 

  77. Jones JL, Anderson JM, Phuah CL, Fox EJ, Selmaj K, Margolin D et al. Improvement in disability after alemtuzumab treatment of multiple sclerosis is associated with neuroprotective autoimmunity. Brain 2010; 133: 2232–2247.

    Article  PubMed  Google Scholar 

  78. Slaets H, Hendriks JJA, Stinissen P, Kilpatrick TJ, Hellings N . Therapeutic potential of LIF in multiple sclerosis. Trends Mol Med 2010; 16: 493–500.

    Article  CAS  PubMed  Google Scholar 

  79. Slaets H, Hendriks JJA, Van den Haute C, Coun F, Baekelandt V, Stinissen P . CNS-targeted LIF expression improves therapeutic efficacy and limits autoimmune-mediated demyelination in a model of multiple sclerosis. Mol Ther 2010; 18: 684–691.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Furlan R, Pluchino S, Martino G . The therapeutic use of gene therapy in inflammatory demyelinating diseases of the central nervous system. Curr Opin Neurol 2003; 16: 385–392.

    Article  CAS  PubMed  Google Scholar 

  81. Elias KM, Laurence A, Davidson TS, Stephens G, Kanno Y, Shevach E et al. Retinoic acid inhibits Th17 polarisation and enhances Foxp3 expression through a Stat-3/Stat-5 independent signaling pathway. Blood 2008; 111: 1013–1020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M et al. Reciprocal Th-17 and regulatory T cell differentiation mediated by retinoic acid. Sciencexpress 14 June 2007.

  83. Van YH, Lee WH, Ortiz S, Lee MH, Qin HJ, Liu CP . All-trans retinoic acid inhibits type 1 diabetes by T regulatory (Treg)-dependent suppression of interferon-gamma-producing T-cells without affecting Th17 cells. Diabetes 2009; 58: 146–155.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Pino-Lagos K, Guo Y, Noelle RJ . Retinoic acid: a key player in immunity. BioFactors 2010; 36: 430–436.

    Article  CAS  PubMed  Google Scholar 

  85. Conlon RA, Rossant J . Exogenous retinoic acid rapidly induces anterior ectopic expression of murine Hox-2 genes in vivo. Development 1992; 116: 357–368.

    Article  CAS  PubMed  Google Scholar 

  86. Xiao S, Jin H, Korn T, Liu SM, Oukka M, Lim B et al. Retinoic acid increases Foxp3+ regulatory T cells and inhibits development of Th17 cells by enhancing TGF-β-driven Smad3 signaling and inhibiting IL-6 and IL-23 receptor expression. J Immunol 2008; 181: 2277–2284.

    Article  CAS  PubMed  Google Scholar 

  87. Schambach F, Schupp M, Lazar MA, Reiner SL . Activation of retinoic acid receptor-α favours regulatory T cell induction at the expense of IL-17-secreting Thelper cell differentiation. Eur J Immunol 2007; 37: 2396–2399.

    Article  CAS  PubMed  Google Scholar 

  88. Littman DR, Rudensky AY . Th17 and regulatory T cells in mediating and restraining inflammation. Cell 2010; 140: 845–858.

    Article  CAS  PubMed  Google Scholar 

  89. Lane MA, Chen AC, Roman SD, Derguini F, Gudas LJ . Removal of LIF (leukemia inhibitory factor) results in increased vitamin A (retinol) metabolism to 4-oxoretinol in embryonic stem cells. Proc Natl Acad Sci USA 1999; 96: 13524–13529.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Martín-Ibáñez R, Urbán N, Sergent-Tanguy S, Pineda JR, Garrido-Clua N, Alberch J et al. Interplay of leukemia inhibitory factor and retinoic acid on neural differentiation of mouse embryonic stem cells. J Neurosci Res 2007; 85: 2686–2701.

    Article  PubMed  CAS  Google Scholar 

  91. Mey J, Henkes L . Retinoic acid enhances leukaemia inhibitory factor expresion in OLN-93 oligodendrocytes. Cell Tissue Res 2002; 310: 155–161.

    Article  CAS  PubMed  Google Scholar 

  92. Wang R, Liang J, Yu HM, Shi YJ, Yang HT . Retinoic acid maintains self-renewal of murine embryonic stem cells via a feedback mechanism. Differentiation 2008; 76: 931–945.

    Article  CAS  PubMed  Google Scholar 

  93. Huang ME, Ye YC, Chen SR, Chai JR, Lu JX, Zhoa L et al. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 1988; 72: 567–572.

    Article  CAS  PubMed  Google Scholar 

  94. Castaigne S, Chomienne C, Daniel MT, Ballerini P, Berger R, Fenaux P et al. All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia I clinical results. Blood 1990; 76: 1704–1709.

    Article  CAS  PubMed  Google Scholar 

  95. Metcalfe SM, Muthukumarana PA, Thompson HL, Haendel MA, Lyons GE . Leukaemia inhibitory factor (LIF) is functionally linked to axotrophin and both LIF and axotrophin are linked to regulatory immune tolerance. FEBS Lett 2005; 579: 609–614.

    Article  CAS  PubMed  Google Scholar 

  96. Robertson NJ, Brook FA, Gardner RL, Cobbold SP, Waldmann H, Fairchild PJ . Embryonic stem cell- derived tissues are immunogenic but their inherent immune privilege promotes the induction of tolerance. Proc Natl Acad Sci USA 2007; 104: 20920–20925.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Nasef A, Mazurier C, Bouchet S, François S, Chapel A, Thierry D et al. Leukemia inhibitory factor: role in human mesenchymal stem cells mediated immunosuppression. Cell Immunol 2008; 253: 16–22.

    Article  CAS  PubMed  Google Scholar 

  98. Glennie S, Soeiro I, Dyson PJ, Lam EWF, Dazzi F . Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood 2005; 105: 2821–2827.

    Article  CAS  PubMed  Google Scholar 

  99. Shih CC, Hu MCT, Hu J, Weng Y, Yazaki PJ, Medeiros J, Forman SJ . A secreted and LIF-mediated stromal cell-derived activity that promotes ex vivo expansion of human hematopoietic stem cells. Blood 2000; 95: 1957–1966.

    Article  CAS  PubMed  Google Scholar 

  100. Lubbert M, Mantovani L, Lindemann A, Mertelsmann R, Herrmann F . Expression of leukemia inhibitory factor is regulated in human mesenchymal cells. Leukemia 1991; 5: 361–365.

    CAS  PubMed  Google Scholar 

  101. Metcalfe SM . Axotrophin and leukaemia inhibitory factor (LIF) in transplantation tolerance. Phil TransR Soc B 2005; 360: 1687–1694.

    Article  CAS  Google Scholar 

  102. Yang X, Nurieva R, Martinez G, Chung Y, Kang H, Pappu B et al. Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity 2008; 29: 44–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Korn T, Mitsdoerffer M, Croxford AL, Awasthi A, Dardalhon VA, Galileos G et al. IL6 controls Th17 immunity in vivo by inhibiting the conversion of conventional T cells into Foxp3+ regulatory T cells. Proc Natl Acad Sci USA 2008; 105: 18460–18465.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Metcalfe, S. LIF in the regulation of T-cell fate and as a potential therapeutic. Genes Immun 12, 157–168 (2011). https://doi.org/10.1038/gene.2011.9

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