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SOCS1: Regulator of T Cells in Autoimmunity and Cancer

  • Subburaj IlangumaranEmail author
  • Diwakar Bobbala
  • Sheela Ramanathan
Chapter
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 410)

Abstract

SOCS1 is a negative feedback regulator of cytokine and growth factor receptor signaling, and plays an indispensable role in attenuating interferon gamma signaling. Studies on SOCS1-deficient mice have established a crucial role for SOCS1 in regulating CD8+ T cell homeostasis. In the thymus, SOCS1 prevents thymocytes that had failed positive selection from surviving and expanding, ensures negative selection and prevents inappropriate developmental skewing toward the CD8 lineage. In the periphery, SOCS1 not only controls production of T cell stimulatory cytokines but also attenuates the sensitivity of CD8+ T cells to synergistic cytokine stimulation and antigen non-specific activation. As cytokine stimulation of CD8+ T lymphocytes increases their sensitivity to low affinity TCR ligands, SOCS1 likely contributes to peripheral T cell tolerance by putting brakes on aberrant T cell activation driven by inflammatory cytokines. In addition, SOCS1 is critical to maintain the stability of T regulatory cells and control their plasticity to become pathogenic Th17 and Th1 cells under the harmful influence of inflammatory cytokines. SOCS1 also regulates T cell activation by dendritic cells via modulating their generation, maturation, antigen presentation, costimulatory signaling, and cytokine production. The above control mechanisms of SOCS1 on T cells, T regulatory cells and dendritic cells collectively contribute to immunological tolerance and prevent autoimmune manifestation. On other hand, silencing SOCS1 in dendritic cells or CD8+ T cells stimulates efficient antitumor immunity. Thus, even though SOCS1 is not a cell surface checkpoint inhibitor, its regulatory functions on T cell responses qualify SOCS1as a “non-classical” checkpoint blocker. SOCS1 also functions as a tumor suppressor in cancer cells by regulating oncogenic signal transduction pathways. The loss of SOCS1 expression observed in many tumors may have an impact on classical checkpoint pathways. The potential to exploit SOCS1 to treat inflammatory/autoimmune diseases and elicit antitumor immunity is discussed.

Notes

Acknowledgments

SI and SR acknowledge funding support from Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant.

References

  1. Acuto O, Di Bartolo V, Michel F (2008) Tailoring T-cell receptor signals by proximal negative feedback mechanisms. Nat Rev Immunol 8:699–712PubMedGoogle Scholar
  2. Acuto O, Michel F (2003) CD28-mediated co-stimulation: a quantitative support for TCR signalling. Nat Rev Immunol 3:939–951PubMedGoogle Scholar
  3. Ahmed CM, Larkin J 3rd, Johnson HM (2015) SOCS1 mimetics and antagonists: a complementary approach to positive and negative regulation of immune function. Front Immunol 6:183PubMedPubMedCentralGoogle Scholar
  4. Alexander WS (2002) Suppressors of cytokine signalling (SOCS) in the immune system. Nat Rev Immunol 2:1–7Google Scholar
  5. Alexander WS, Starr R, Fenner JE, Scott CL, Handman E, Sprigg NS, Corbin JE, Cornish AL, Darwiche R, Owczarek CM et al (1999) SOCS1 is a critical inhibitor of interferon gamma signaling and prevents the potentially fatal neonatal actions of this cytokine. Cell 98:597–608PubMedGoogle Scholar
  6. Anguille S, Smits EL, Lion E, van Tendeloo VF, Berneman ZN (2014) Clinical use of dendritic cells for cancer therapy. Lancet Oncol 15:e257–e267PubMedGoogle Scholar
  7. Babon JJ, Sabo JK, Zhang JG, Nicola NA, Norton RS (2009) The SOCS box encodes a hierarchy of affinities for Cullin5: implications for ubiquitin ligase formation and cytokine signalling suppression. J Mol Biol 387:162–174PubMedPubMedCentralGoogle Scholar
  8. Babon JJ, Kershaw NJ, Murphy JM, Varghese LN, Laktyushin A, Young SN, Lucet IS, Norton RS, Nicola NA (2012) Suppression of cytokine signaling by SOCS3: characterization of the mode of inhibition and the basis of its specificity. Immunity 36:239–250PubMedPubMedCentralGoogle Scholar
  9. Babon JJ, Lucet IS, Murphy JM, Nicola NA, Varghese LN (2014a) The molecular regulation of Janus kinase (JAK) activation. Biochem J 462:1–13PubMedPubMedCentralGoogle Scholar
  10. Babon JJ, Varghese LN, Nicola NA (2014b) Inhibition of IL-6 family cytokines by SOCS3. Semin Immunol 26:13–19PubMedPubMedCentralGoogle Scholar
  11. Baetz A, Koelsche C, Strebovsky J, Heeg K, Dalpke AH (2008) Identification of a nuclear localization signal in suppressor of cytokine signaling 1. Faseb J 22:4296–4305PubMedGoogle Scholar
  12. Bailey-Bucktrout SL, Martinez-Llordella M, Zhou X, Anthony B, Rosenthal W, Luche H, Fehling HJ, Bluestone JA (2013) Self-antigen-driven activation induces instability of regulatory T cells during an inflammatory autoimmune response. Immunity 39:949–962PubMedPubMedCentralGoogle Scholar
  13. Baniyash M (2004) TCR zeta-chain downregulation: curtailing an excessive inflammatory immune response. Nat Rev Immunol 4:675–687PubMedGoogle Scholar
  14. Bartz H, Avalos NM, Baetz A, Heeg K, Dalpke AH (2006) Involvement of suppressors of cytokine signaling in toll-like receptor-mediated block of dendritic cell differentiation. Blood 108:4102–4108PubMedGoogle Scholar
  15. Baxter AG, Hodgkin PD (2002) Activation rules: the two-signal theories of immune activation. Nat Rev Immunol 2:439–446PubMedGoogle Scholar
  16. Ben-Sasson SZ, Hu-Li J, Quiel J, Cauchetaux S, Ratner M, Shapira I, Dinarello CA, Paul WE (2009) IL-1 acts directly on CD4 T cells to enhance their antigen-driven expansion and differentiation. Proc Natl Acad Sci USA 106:7119–7124PubMedGoogle Scholar
  17. Bourdonnay E, Zaslona Z, Penke LR, Speth JM, Schneider DJ, Przybranowski S, Swanson JA, Mancuso P, Freeman CM, Curtis JL, Peters-Golden M (2015) Transcellular delivery of vesicular SOCS proteins from macrophages to epithelial cells blunts inflammatory signaling. J Exp Med 212:729–742PubMedPubMedCentralGoogle Scholar
  18. Bourette RP, De Sepulveda P, Arnaud S, Dubreuil P, Rottapel R, Mouchiroud G (2001) Suppressor of cytokine signaling 1 interacts with the macrophage colony-stimulating factor receptor and negatively regulates its proliferation signal. J Biol Chem 276:22133–22139PubMedGoogle Scholar
  19. Boyle K, Egan P, Rakar S, Willson TA, Wicks IP, Metcalf D, Hilton DJ, Nicola NA, Alexander WS, Roberts AW, Robb L (2007) The SOCS box of suppressor of cytokine signaling-3 contributes to the control of G-CSF responsiveness in vivo. Blood 110:1466–1474PubMedPubMedCentralGoogle Scholar
  20. Bunda S, Kommaraju K, Heir P, Ohh M (2013) SOCS-1 mediates ubiquitylation and degradation of GM-CSF receptor. PLoS ONE 8:e76370PubMedPubMedCentralGoogle Scholar
  21. Carow B, Ye X, Gavier-Widen D, Bhuju S, Oehlmann W, Singh M, Skold M, Ignatowicz L, Yoshimura A, Wigzell H, Rottenberg ME (2011) Silencing suppressor of cytokine signaling-1 (SOCS1) in macrophages improves Mycobacterium tuberculosis control in an interferon-gamma (IFN-gamma)-dependent manner. J Biol Chem 286:26873–26887PubMedPubMedCentralGoogle Scholar
  22. Catlett IM, Hedrick SM (2005) Suppressor of cytokine signaling 1 is required for the differentiation of CD4+ T cells. Nat Immunol 6:715–721PubMedGoogle Scholar
  23. Chang JH, Xiao Y, Hu H, Jin J, Yu J, Zhou X, Wu X, Johnson HM, Akira S, Pasparakis M et al (2012) Ubc13 maintains the suppressive function of regulatory T cells and prevents their conversion into effector-like T cells. Nat Immunol 13:481–490PubMedPubMedCentralGoogle Scholar
  24. Chen L, Flies DB (2013) Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol 13:227–242PubMedPubMedCentralGoogle Scholar
  25. Chen Q, Kim YC, Laurence A, Punkosdy GA, Shevach EM (2011) IL-2 controls the stability of Foxp3 expression in TGF-beta-induced Foxp3+ T cells in vivo. J Immunol 186:6329–6337PubMedPubMedCentralGoogle Scholar
  26. Chevrier M, Bobbala D, Villalobos-Hernandez A, Khan MG, Ramanathan S, Saucier C, Ferbeyre G, Geha S, Ilangumaran S (2017) Expression of SOCS1 and the downstream targets of its putative tumor suppressor functions in prostate cancer. BMC Cancer 17:157PubMedPubMedCentralGoogle Scholar
  27. Chinen T, Kobayashi T, Ogata H, Takaesu G, Takaki H, Hashimoto M, Yagita H, Nawata H, Yoshimura A (2006) Suppressor of cytokine signaling-1 regulates inflammatory bowel disease in which both IFNgamma and IL-4 are involved. Gastroenterology 130:373–388PubMedGoogle Scholar
  28. Chong MM, Cornish AL, Darwiche R, Stanley EG, Purton JF, Godfrey DI, Hilton DJ, Starr R, Alexander WS, Kay TW (2003) Suppressor of cytokine signaling-1 is a critical regulator of interleukin-7-dependent CD8+ T cell differentiation. Immunity 18:475–487PubMedGoogle Scholar
  29. Chong MM, Metcalf D, Jamieson E, Alexander WS, Kay TW (2005) Suppressor of cytokine signaling-1 in T cells and macrophages is critical for preventing lethal inflammation. Blood 106:1668–1675PubMedGoogle Scholar
  30. Cornish AL, Chong MM, Davey GM, Darwiche R, Nicola NA, Hilton DJ, Kay TW, Starr R, Alexander WS (2003a) Suppressor of cytokine signaling-1 regulates signaling in response to interleukin-2 and other gamma c-dependent cytokines in peripheral T cells. J Biol Chem 278:22755–22761PubMedGoogle Scholar
  31. Cornish AL, Davey GM, Metcalf D, Purton JF, Corbin JE, Greenhalgh CJ, Darwiche R, Wu L, Nicola NA, Godfrey DI et al (2003b) Suppressor of cytokine signaling-1 has IFN-gamma-independent actions in T cell homeostasis. J Immunol 170:878–886PubMedGoogle Scholar
  32. Cox MA, Harrington LE, Zajac AJ (2011) Cytokines and the inception of CD8 T cell responses. Trends Immunol 32:180–186PubMedPubMedCentralGoogle Scholar
  33. Croker BA, Krebs DL, Zhang JG, Wormald S, Willson TA, Stanley EG, Robb L, Greenhalgh CJ, Forster I, Clausen BE et al (2003) SOCS3 negatively regulates IL-6 signaling in vivo. Nat Immunol 4:540–545Google Scholar
  34. Curtsinger JM, Lins DC, Mescher MF (2003) Signal 3 determines tolerance versus full activation of naive CD8 T cells: dissociating proliferation and development of effector function. J Exp Med 197:1141–1151PubMedPubMedCentralGoogle Scholar
  35. Curtsinger JM, Lins DC, Johnson CM, Mescher MF (2005a) Signal 3 tolerant CD8 T cells degranulate in response to antigen but lack granzyme B to mediate cytolysis. J Immunol 175:4392–4399PubMedGoogle Scholar
  36. Curtsinger JM, Valenzuela JO, Agarwal P, Lins D, Mescher MF (2005b) Type I IFNs provide a third signal to CD8 T cells to stimulate clonal expansion and differentiation. J Immunol 174:4465–4469PubMedGoogle Scholar
  37. Curtsinger JM, Mescher MF (2010) Inflammatory cytokines as a third signal for T cell activation. Curr Opin Immunol 22:333–340PubMedPubMedCentralGoogle Scholar
  38. Davey GM, Starr R, Cornish AL, Burghardt JT, Alexander WS, Carbone FR, Surh CD, Heath WR (2005) SOCS-1 regulates IL-15-driven homeostatic proliferation of antigen-naive CD8 T cells, limiting their autoimmune potential. J Exp Med 202:1099–1108PubMedPubMedCentralGoogle Scholar
  39. De Sepulveda P, Okkenhaug K, Rose JL, Hawley RG, Dubreuil P, Rottapel R (1999) Socs1 binds to multiple signalling proteins and suppresses steel factor- dependent proliferation. EMBO J 18:904–915PubMedPubMedCentralGoogle Scholar
  40. DiGiandomenico A, Wylezinski LS, Hawiger J (2009) Intracellular delivery of a cell-penetrating SOCS1 that targets IFN-gamma signaling. Sci Signal 2:ra37Google Scholar
  41. Dubois SP, Waldmann TA, Muller JR (2005) Survival adjustment of mature dendritic cells by IL-15. Proc Natl Acad Sci USA 102:8662–8667PubMedGoogle Scholar
  42. Egan PJ, Lawlor KE, Alexander WS, Wicks IP (2003) Suppressor of cytokine signaling-1 regulates acute inflammatory arthritis and T cell activation. J Clin Invest 111:915–924PubMedPubMedCentralGoogle Scholar
  43. Endo TA, Masuhara M, Yokouchi M, Suzuki R, Sakamoto H, Mitsui K, Matsumoto A, Tanimura S, Ohtsubo M, Misawa H et al (1997) A new protein containing an SH2 domain that inhibits JAK kinases. Nature 387:921–924PubMedGoogle Scholar
  44. Evel-Kabler K, Song XT, Aldrich M, Huang XF, Chen SY (2006) SOCS1 restricts dendritic cells’ ability to break self tolerance and induce antitumor immunity by regulating IL-12 production and signaling. J Clin Invest 116:90–100PubMedGoogle Scholar
  45. Feng ZP, Chandrashekaran IR, Low A, Speed TP, Nicholson SE, Norton RS (2012) The N-terminal domains of SOCS proteins: a conserved region in the disordered N-termini of SOCS4 and 5. Proteins 80:946–957PubMedGoogle Scholar
  46. Flowers LO, Subramaniam PS, Johnson HM (2005) A SOCS-1 peptide mimetic inhibits both constitutive and IL-6 induced activation of STAT3 in prostate cancer cells. Oncogene 24:2114–2120PubMedGoogle Scholar
  47. Fujimoto M, Naka T (2003) Regulation of cytokine signaling by SOCS family molecules. Trends Immunol 24:659–666PubMedGoogle Scholar
  48. Fujimoto M, Naka T, Nakagawa R, Kawazoe Y, Morita Y, Tateishi A, Okumura K, Narazaki M, Kishimoto T (2000) Defective thymocyte development and perturbed homeostasis of T cells in STAT-induced STAT inhibitor-1/suppressors of cytokine signaling-1 transgenic mice. J Immunol 165:1799–1806PubMedGoogle Scholar
  49. Fujimoto M, Tsutsui H, Xinshou O, Tokumoto M, Watanabe D, Shima Y, Yoshimoto T, Hirakata H, Kawase I, Nakanishi K et al (2004) Inadequate induction of suppressor of cytokine signaling-1 causes systemic autoimmune diseases. Int Immunol 16:303–314PubMedGoogle Scholar
  50. Gagnon J, Ramanathan S, Leblanc C, Cloutier A, McDonald PP, Ilangumaran S (2008) IL-6, in synergy with IL-7 or IL-15, stimulates TCR-independent proliferation and functional differentiation of CD8+ T lymphocytes. J Immunol 180:7958–7968PubMedGoogle Scholar
  51. Gagnon J, Ramanathan S, Leblanc C, Ilangumaran S (2007) Regulation of IL-21 signaling by suppressor of cytokine signaling-1 (SOCS1) in CD8(+) T lymphocytes. Cell Signal 19:806–816PubMedGoogle Scholar
  52. Gui Y, Yeganeh M, Donates YC, Tobelaim WS, Chababi W, Mayhue M, Yoshimura A, Ramanathan S, Saucier C, Ilangumaran S (2015) Regulation of MET receptor tyrosine kinase signaling by suppressor of cytokine signaling 1 in hepatocellular carcinoma. Oncogene 34:5718–5728PubMedGoogle Scholar
  53. Hanada T, Yoshida H, Kato S, Tanaka K, Masutani K, Tsukada J, Nomura Y, Mimata H, Kubo M, Yoshimura A (2003) Suppressor of cytokine signaling-1 is essential for suppressing dendritic cell activation and systemic autoimmunity. Immunity 19:437–450PubMedGoogle Scholar
  54. Hanada T, Tanaka K, Matsumura Y, Yamauchi M, Nishinakamura H, Aburatani H, Mashima R, Kubo M, Kobayashi T, Yoshimura A (2005) Induction of hyper Th1 cell-type immune responses by dendritic cells lacking the suppressor of cytokine signaling-1 gene. J Immunol 174:4325–4332PubMedGoogle Scholar
  55. Hanada T, Kobayashi T, Chinen T, Saeki K, Takaki H, Koga K, Minoda Y, Sanada T, Yoshioka T, Mimata H et al (2006) IFNgamma-dependent, spontaneous development of colorectal carcinomas in SOCS1-deficient mice. J Exp Med 203:1391–1397PubMedPubMedCentralGoogle Scholar
  56. Haring JS, Badovinac VP, Harty JT (2006) Inflaming the CD8+ T cell response. Immunity 25:19–29PubMedGoogle Scholar
  57. Heath WR, Carbone FR (2009) Dendritic cell subsets in primary and secondary T cell responses at body surfaces. Nat Immunol 10:1237–1244PubMedGoogle Scholar
  58. Hori S (2014) Lineage stability and phenotypic plasticity of Foxp3(+) regulatory T cells. Immunol Rev 259:159–172PubMedGoogle Scholar
  59. Horino J, Fujimoto M, Terabe F, Serada S, Takahashi T, Soma Y, Tanaka K, Chinen T, Yoshimura A, Nomura S et al (2008) Suppressor of cytokine signaling-1 ameliorates dextran sulfate sodium-induced colitis in mice. Int Immunol 20:753–762PubMedGoogle Scholar
  60. Hsieh CS, Lee HM, Lio CW (2012) Selection of regulatory T cells in the thymus. Nat Rev Immunol 12:157–167PubMedGoogle Scholar
  61. Huang FJ, Steeg PS, Price JE, Chiu WT, Chou PC, Xie K, Sawaya R, Huang S (2008) Molecular basis for the critical role of suppressor of cytokine signaling-1 in melanoma brain metastasis. Can Res 68:9634–9642Google Scholar
  62. Hwang MN, Min CH, Kim HS, Lee H, Yoon KA, Park SY, Lee ES, Yoon S (2007) The nuclear localization of SOCS6 requires the N-terminal region and negatively regulates Stat3 protein levels. Biochem Biophys Res Commun 360:333–338PubMedGoogle Scholar
  63. Ilangumaran S, Gagnon J, Leblanc C, Poussier P, Ramanathan S (2010) Increased generation of CD8 single positive cells in SOCS1-deficient thymus does not proportionately increase their export. Immunol Lett 132:12–17PubMedGoogle Scholar
  64. Ilangumaran S, Ramanathan S, La Rose J, Poussier P, Rottapel R (2003a) Suppressor of cytokine signaling 1 regulates IL-15 receptor signaling in CD8 + CD44high memory T lymphocytes. J Immunol 171:2435–2445PubMedGoogle Scholar
  65. Ilangumaran S, Ramanathan S, Ning T, La Rose J, Reinhart B, Poussier P, Rottapel R (2003b) Suppressor of cytokine signaling 1 attenuates IL-15 receptor signaling in CD8+ thymocytes. Blood 102:4115–4122PubMedGoogle Scholar
  66. Ilangumaran S, Ramanathan S, Rottapel R (2004) Regulation of the immune system by SOCS family adaptor proteins. Semin Immunol 16:351–365PubMedGoogle Scholar
  67. Ilangumaran S, Villalobos-Hernandez A, Bobbala D, Ramanathan S (2016) The hepatocyte growth factor (HGF)-MET receptor tyrosine kinase signaling pathway: Diverse roles in modulating immune cell functions. Cytokine 82:125–139PubMedGoogle Scholar
  68. Inagaki-Ohara K, Kondo T, Ito M, Yoshimura A (2013) SOCS, inflammation, and cancer. Jak-Stat 2:e24053PubMedPubMedCentralGoogle Scholar
  69. Jackson SH, Yu CR, Mahdi RM, Ebong S, Egwuagu CE (2004) Dendritic cell maturation requires STAT1 and is under feedback regulation by suppressors of cytokine signaling. J Immunol 172:2307–2315PubMedGoogle Scholar
  70. Jager LD, Dabelic R, Waiboci LW, Lau K, Haider MS, Ahmed CM, Larkin J 3rd, David S, Johnson HM (2011) The kinase inhibitory region of SOCS-1 is sufficient to inhibit T-helper 17 and other immune functions in experimental allergic encephalomyelitis. J Neuroimmunol 232:108–118PubMedGoogle Scholar
  71. Jameson SC (2002) Maintaining the norm: T-cell homeostasis. Nat Rev Immunol 2:547–556PubMedGoogle Scholar
  72. Ji Y, Wrzesinski C, Yu Z, Hu J, Gautam S, Hawk NV, Telford WG, Palmer DC, Franco Z, Sukumar M et al (2015) miR-155 augments CD8+ T-cell antitumor activity in lymphoreplete hosts by enhancing responsiveness to homeostatic gammac cytokines. Proc Natl Acad Sci USA 112:476–481PubMedGoogle Scholar
  73. Jiang S, Zhang HW, Lu MH, He XH, Li Y, Gu H, Liu MF, Wang ED (2010) MicroRNA-155 functions as an OncomiR in breast cancer by targeting the suppressor of cytokine signaling 1 gene. Can Res 70:3119–3127Google Scholar
  74. Kazi JU, Kabir NN, Flores-Morales A, Ronnstrand L (2014) SOCS proteins in regulation of receptor tyrosine kinase signaling. Cell Mol L Sci: CMLS 71:3297–3310Google Scholar
  75. Kershaw NJ, Murphy JM, Liau NP, Varghese LN, Laktyushin A, Whitlock EL, Lucet IS, Nicola NA, Babon JJ (2013) SOCS3 binds specific receptor-JAK complexes to control cytokine signaling by direct kinase inhibition. Nat Struct Mol Biol 20:469–476PubMedPubMedCentralGoogle Scholar
  76. Kile BT, Schulman BA, Alexander WS, Nicola NA, Martin HM, Hilton DJ (2002) The SOCS box: a tale of destruction and degradation. Trends Biochem Sci 27:235–241PubMedGoogle Scholar
  77. Kinjyo I, Hanada T, Inagaki-Ohara K, Mori H, Aki D, Ohishi M, Yoshida H, Kubo M, Yoshimura A (2002) SOCS1/JAB is a negative regulator of LPS-induced macrophage activation. Immunity 17:583–591PubMedPubMedCentralGoogle Scholar
  78. Kobayashi N, Uemura H, Nagahama K, Okudela K, Furuya M, Ino Y, Ito Y, Hirano H, Inayama Y, Aoki I et al (2012) Identification of miR-30d as a novel prognostic maker of prostate cancer. Oncotarget 3:1455–1471PubMedPubMedCentralGoogle Scholar
  79. Kolumam GA, Thomas S, Thompson LJ, Sprent J, Murali-Krishna K (2005) Type I interferons act directly on CD8 T cells to allow clonal expansion and memory formation in response to viral infection. J Exp Med 202:637–650PubMedPubMedCentralGoogle Scholar
  80. Komarowska I, Coe D, Wang G, Haas R, Mauro C, Kishore M, Cooper D, Nadkarni S, Fu H, Steinbruchel DA et al (2015) Hepatocyte growth factor receptor c-Met instructs T Cell cardiotropism and promotes T Cell migration to the heart via autocrine chemokine release. Immunity 42:1087–1099PubMedPubMedCentralGoogle Scholar
  81. Komatsu N, Mariotti-Ferrandiz ME, Wang Y, Malissen B, Waldmann H, Hori S (2009) Heterogeneity of natural Foxp3+ T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity. Proc Natl Acad Sci USA 106:1903–1908PubMedGoogle Scholar
  82. Komatsu N, Okamoto K, Sawa S, Nakashima T, Oh-hora M, Kodama T, Tanaka S, Bluestone JA, Takayanagi H (2014) Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nat Med 20:62–68PubMedGoogle Scholar
  83. Kremer BE, Adang LA, Macara IG (2007) Septins regulate actin organization and cell-cycle arrest through nuclear accumulation of NCK mediated by SOCS7. Cell 130:837–850PubMedPubMedCentralGoogle Scholar
  84. Liu E, Cote JF, Vuori K (2003) Negative regulation of FAK signaling by SOCS proteins. EMBO J 22:5036–5046PubMedPubMedCentralGoogle Scholar
  85. Liu L, Li W, Wei X, Cui Q, Lou W, Wang G, Hu X, Qian C (2013) Potent antitumor activity of oncolytic adenovirus-mediated SOCS1 for hepatocellular carcinoma. Gene Ther 20:84–92PubMedGoogle Scholar
  86. Lu LF, Boldin MP, Chaudhry A, Lin LL, Taganov KD, Hanada T, Yoshimura A, Baltimore D, Rudensky AY (2010) Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses. Cell 142:914–929PubMedPubMedCentralGoogle Scholar
  87. Lu X, Chen M, Xue Z, Zhang X, Xu J, Wu L, Deng R, Ma Y (2017a) Dendritic cells that highly express SOCS1 induce T-cell hypo-responsiveness and prolong islet allograft survival. Cell ImmunolGoogle Scholar
  88. Lu X, Chen M, Xue Z, Zhang X, Xu J, Wu L, Deng R, Ma Y (2017b) Dendritic cells that highly express SOCS1 induce T-cell hypo-responsiveness and prolong islet allograft survival. Cell Immunol 314:36–41PubMedGoogle Scholar
  89. Madonna S, Scarponi C, Doti N, Carbone T, Cavani A, Scognamiglio PL, Marasco D, Albanesi C (2013) Therapeutical potential of a peptide mimicking the SOCS1 kinase inhibitory region in skin immune responses. Eur J Immunol 43:1883–1895PubMedGoogle Scholar
  90. Mahoney KM, Rennert PD, Freeman GJ (2015) Combination cancer immunotherapy and new immunomodulatory targets. Nat Rev Drug Discov 14:561–584PubMedGoogle Scholar
  91. Maine GN, Mao X, Komarck CM, Burstein E (2007) COMMD1 promotes the ubiquitination of NF-kappaB subunits through a cullin-containing ubiquitin ligase. EMBO J 26:436–447PubMedGoogle Scholar
  92. Mansell A, Smith R, Doyle SL, Gray P, Fenner JE, Crack PJ, Nicholson SE, Hilton DJ, O’Neill LA, Hertzog PJ (2006) Suppressor of cytokine signaling 1 negatively regulates Toll-like receptor signaling by mediating Mal degradation. Nat Immunol 7:148–155PubMedGoogle Scholar
  93. Marine JC, Topham DJ, McKay C, Wang D, Parganas E, Stravopodis D, Yoshimura A, Ihle JN (1999) SOCS1 deficiency causes a lymphocyte-dependent perinatal lethality. Cell 98:609–616PubMedGoogle Scholar
  94. Martens N, Wery M, Wang P, Braet F, Gertler A, Hooghe R, Vandenhaute J, Hooghe-Peters EL (2004) The suppressor of cytokine signaling (SOCS)-7 interacts with the actin cytoskeleton through vinexin. Exp Cell Res 298:239–248PubMedGoogle Scholar
  95. Matsuda T, Yamamoto T, Kishi H, Yoshimura A, Muraguchi A (2000) SOCS-1 can suppress CD3zeta- and Syk-mediated NF-AT activation in a non- lymphoid cell line. FEBS Lett 472:235–240PubMedGoogle Scholar
  96. Mattei F, Schiavoni G, Belardelli F, Tough DF (2001) IL-15 is expressed by dendritic cells in response to type I IFN, double-stranded RNA, or lipopolysaccharide and promotes dendritic cell activation. J Immunol 167:1179–1187PubMedGoogle Scholar
  97. McGray AJ, Hallett R, Bernard D, Swift SL, Zhu Z, Teoderascu F, Vanseggelen H, Hassell JA, Hurwitz AA, Wan Y, Bramson JL (2014) Immunotherapy-induced CD8+ T cells instigate immune suppression in the tumor. Mol Ther: J Am Soc Gene Ther 22:206–218Google Scholar
  98. Mescher MF, Agarwal P, Casey KA, Hammerbeck CD, Xiao Z, Curtsinger JM (2007) Molecular basis for checkpoints in the CD8 T cell response: tolerance versus activation. Semin Immunol 19:153–161PubMedPubMedCentralGoogle Scholar
  99. Metcalf D, Mifsud S, Di Rago L, Nicola NA, Hilton DJ, Alexander WS (2002) Polycystic kidneys and chronic inflammatory lesions are the delayed consequences of loss of the suppressor of cytokine signaling-1 (SOCS-1). Proc Natl Acad Sci USA 99:943–948PubMedGoogle Scholar
  100. Murali-Krishna K, Ahmed R (2000) Cutting edge: naive T cells masquerading as memory cells. J Immunol 165:1733–1737PubMedGoogle Scholar
  101. Murugaiyan G, Beynon V, Mittal A, Joller N, Weiner HL (2011) Silencing microRNA-155 ameliorates experimental autoimmune encephalomyelitis. J Immunol 187:2213–2221PubMedPubMedCentralGoogle Scholar
  102. Naka T, Matsumoto T, Narazaki M, Fujimoto M, Morita Y, Ohsawa Y, Saito H, Nagasawa T, Uchiyama Y, Kishimoto Ts (1998) Accelerated apoptosis of lymphocytes by augmented induction of Bax in SSI-1 (STAT-induced STAT inhibitor-1) deficient mice. Proc Natl Acad Sci USA 95:15577–15582Google Scholar
  103. Naka T, Narazaki M, Hirata M, Matsumoto T, Minamoto S, Aono A, Nishimoto N, Kajita T, Taga T, Yoshizaki K et al (1997) Structure and function of a new STAT-induced STAT inhibitor. Nature 387:924–929PubMedGoogle Scholar
  104. Nakagawa R, Naka T, Tsutsui H, Fujimoto M, Kimura A, Abe T, Seki E, Sato S, Takeuchi O, Takeda K et al (2002) SOCS-1 participates in negative regulation of LPS responses. Immunity 17:677–687PubMedGoogle Scholar
  105. Naramura M, Jang IK, Kole H, Huang F, Haines D, Gu H (2002) c-Cbl and Cbl-b regulate T cell responsiveness by promoting ligand-induced TCR down-modulation. Nat Immunol 3:1192–1199PubMedGoogle Scholar
  106. Natatsuka R, Takahashi T, Serada S, Fujimoto M, Ookawara T, Nishida T, Hara H, Nishigaki T, Harada E, Murakami T et al (2015) Gene therapy with SOCS1 for gastric cancer induces G2/M arrest and has an antitumour effect on peritoneal carcinomatosis. Br J Cancer 113:433–442PubMedPubMedCentralGoogle Scholar
  107. Nicholson SE, Willson TA, Farley A, Starr R, Zhang JG, Baca M, Alexander WS, Metcalf D, Hilton DJ, Nicola NA (1999) Mutational analyses of the SOCS proteins suggest a dual domain requirement but distinct mechanisms for inhibition of LIF and IL-6 signal transduction. EMBO J 18:375–385PubMedPubMedCentralGoogle Scholar
  108. O’Connell RM, Kahn D, Gibson WS, Round JL, Scholz RL, Chaudhuri AA, Kahn ME, Rao DS, Baltimore D (2010) MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development. Immunity 33:607–619PubMedPubMedCentralGoogle Scholar
  109. Ohkura N, Kitagawa Y, Sakaguchi S (2013) Development and maintenance of regulatory T cells. Immunity 38:414–423PubMedGoogle Scholar
  110. Ohya K, Kajigaya S, Yamashita Y, Miyazato A, Hatake K, Miura Y, Ikeda U, Shimada K, Ozawa K, Mano H (1997) SOCS-1/JAB/SSI-1 can bind to and suppress Tec protein-tyrosine kinase. J Biol Chem 272:27178–27182PubMedGoogle Scholar
  111. Okumura F, Matsuzaki M, Nakatsukasa K, Kamura T (2012) The role of elongin BC-containing ubiquitin ligases. Front Oncol 2:10PubMedPubMedCentralGoogle Scholar
  112. Ostiguy V, Allard EL, Marquis M, Leignadier J, Labrecque N (2007) IL-21 promotes T lymphocyte survival by activating the phosphatidylinositol-3 kinase signaling cascade. J Leukoc Biol 82:645–656PubMedGoogle Scholar
  113. Palmer DC, Guittard GC, Franco Z, Crompton JG, Eil RL, Patel SJ, Ji Y, Van Panhuys N, Klebanoff CA, Sukumar M et al (2015) Cish actively silences TCR signaling in CD8 + T cells to maintain tumor tolerance. J Exp Med 212:2095–2113PubMedPubMedCentralGoogle Scholar
  114. Palmer DC, Restifo NP (2009) Suppressors of cytokine signaling (SOCS) in T cell differentiation, maturation, and function. Trends Immunol 30:592–602PubMedPubMedCentralGoogle Scholar
  115. Palucka K, Banchereau J (2012) Cancer immunotherapy via dendritic cells. Nat Rev Cancer 12:265–277PubMedPubMedCentralGoogle Scholar
  116. Park JH, Adoro S, Guinter T, Erman B, Alag AS, Catalfamo M, Kimura MY, Cui Y, Lucas PJ, Gress RE et al (2010) Signaling by intrathymic cytokines, not T cell antigen receptors, specifies CD8 lineage choice and promotes the differentiation of cytotoxic-lineage T cells. Nat Immunol 11:257–264PubMedPubMedCentralGoogle Scholar
  117. Paterson AM, Vanguri VK, Sharpe AH (2009) SnapShot: B7/CD28 costimulation. Cell 137(974–974):e971Google Scholar
  118. Pichiorri F, Suh SS, Ladetto M, Kuehl M, Palumbo T, Drandi D, Taccioli C, Zanesi N, Alder H, Hagan JP et al (2008) MicroRNAs regulate critical genes associated with multiple myeloma pathogenesis. Proc Natl Acad Sci USA 105:12885–12890PubMedGoogle Scholar
  119. Rafei M, Rouette A, Brochu S, Vanegas JR, Perreault C (2013) Differential effects of gammac cytokines on postselection differentiation of CD8 thymocytes. Blood 121:107–117PubMedGoogle Scholar
  120. Ramanathan S, Dubois S, Chen XL, Leblanc C, Ohashi PS, Ilangumaran S (2011) Exposure to IL-15 and IL-21 enables autoreactive CD8 T cells to respond to weak antigens and cause disease in a mouse model of autoimmune diabetes. J Immunol 186:5131–5141PubMedGoogle Scholar
  121. Ramanathan S, Dubois S, Gagnon J, Leblanc C, Mariathasan S, Ferbeyre G, Rottapel R, Ohashi PS, Ilangumaran S (2010) Regulation of cytokine-driven functional differentiation of CD8 T cells by suppressor of cytokine signaling 1 controls autoimmunity and preserves their proliferative capacity toward foreign antigens. J Immunol 185:357–366PubMedGoogle Scholar
  122. Ramanathan S, Gagnon J, Leblanc C, Rottapel R, Ilangumaran S (2006) Suppressor of cytokine signaling 1 stringently regulates distinct functions of IL-7 and IL-15 in vivo during T lymphocyte development and homeostasis. J Immunol 176:4029–4041PubMedGoogle Scholar
  123. Ribas A (2015) Adaptive immune resistance: how cancer protects from immune attack. Cancer Discov 5:915–919PubMedPubMedCentralGoogle Scholar
  124. Rodriguez GM, D’Urbano D, Bobbala D, Chen XL, Yeganeh M, Ramanathan S, Ilangumaran S (2013) SOCS1 prevents potentially skin-reactive cytotoxic T lymphocytes from gaining the ability to cause inflammatory lesions. J Invest Dermatol 133:2013–2022PubMedGoogle Scholar
  125. Rosenberg SA, Restifo NP (2015) Adoptive cell transfer as personalized immunotherapy for human cancer. Science 348:62–68PubMedGoogle Scholar
  126. Ryo A, Suizu F, Yoshida Y, Perrem K, Liou YC, Wulf G, Rottapel R, Yamaoka S, Lu KP (2003) Regulation of NF-kappaB signaling by Pin1-dependent prolyl isomerization and ubiquitin-mediated proteolysis of p65/RelA. Mol Cell 12:1413–1426PubMedGoogle Scholar
  127. Sakaguchi S, Vignali DA, Rudensky AY, Niec RE, Waldmann H (2013) The plasticity and stability of regulatory T cells. Nat Rev Immunol 13:461–467PubMedGoogle Scholar
  128. Sasaki A, Yasukawa H, Suzuki A, Kamizono S, Syoda T, Kinjyo I, Sasaki M, Johnston JA, Yoshimura A (1999) Cytokine-inducible SH2 protein-3 (CIS3/SOCS3) inhibits Janus tyrosine kinase by binding through the N-terminal kinase inhibitory region as well as SH2 domain. Genes Cells 4:339–351PubMedGoogle Scholar
  129. Sasi W, Sharma AK, Mokbel K (2014) The role of suppressors of cytokine signalling in human neoplasms. Mol Biol Int 2014:630797PubMedPubMedCentralGoogle Scholar
  130. Schmitt EG, Williams CB (2013) Generation and function of induced regulatory T cells. Front Immunol 4:152PubMedPubMedCentralGoogle Scholar
  131. Schwartz RH (2003) T cell anergy. Annu Rev Immunol 21:305–334PubMedGoogle Scholar
  132. Sharma MD, Hou DY, Baban B, Koni PA, He Y, Chandler PR, Blazar BR, Mellor AL, Munn DH (2010) Reprogrammed foxp3(+) regulatory T cells provide essential help to support cross-presentation and CD8(+) T cell priming in naive mice. Immunity 33:942–954PubMedPubMedCentralGoogle Scholar
  133. Shen L, Evel-Kabler K, Strube R, Chen SY (2004) Silencing of SOCS1 enhances antigen presentation by dendritic cells and antigen-specific anti-tumor immunity. Nat Biotechnol 22:1546–1553PubMedGoogle Scholar
  134. Shi D, Li D, Yin Q, Qiu Y, Yan H, Shen Y, Lu G, Liu W (2015) Silenced suppressor of cytokine signaling 1 (SOCS1) enhances the maturation and antifungal immunity of dendritic cells in response to Candida albicans in vitro. Immunol Res 61:206–218PubMedGoogle Scholar
  135. Souma Y, Nishida T, Serada S, Iwahori K, Takahashi T, Fujimoto M, Ripley B, Nakajima K, Miyazaki Y, Mori M et al (2012) Antiproliferative effect of SOCS-1 through the suppression of STAT3 and p38 MAPK activation in gastric cancer cells. Int J Cancer 131:1287–1296PubMedGoogle Scholar
  136. Sporri B, Kovanen PE, Sasaki A, Yoshimura A, Leonard WJ (2001) JAB/SOCS1/SSI-1 is an interleukin-2-induced inhibitor of IL-2 signaling. Blood 97:221–226PubMedGoogle Scholar
  137. Spranger S, Spaapen RM, Zha Y, Williams J, Meng Y, Ha TT, Gajewski TF (2013) Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Sci Transl Med 5:200ra116Google Scholar
  138. Stanford SM, Rapini N, Bottini N (2012) Regulation of TCR signalling by tyrosine phosphatases: from immune homeostasis to autoimmunity. Immunology 137:1–19PubMedPubMedCentralGoogle Scholar
  139. Starr R, Metcalf D, Elefanty AG, Brysha M, Willson TA, Nicola NA, Hilton DJ, Alexander WS (1998) Liver degeneration and lymphoid deficiencies in mice lacking suppressor of cytokine signaling-1. Proc Natl Acad Sci USA 95:14395–14399PubMedGoogle Scholar
  140. Starr R, Willson TA, Viney EM, Murray LJ, Rayner JR, Jenkins BJ, Gonda TJ, Alexander WS, Metcalf D, Nicola NA, Hilton DJ (1997) A family of cytokine-inducible inhibitors of signalling. Nature 387:917–921PubMedGoogle Scholar
  141. Strebovsky J, Walker P, Lang R, Dalpke AH (2011) Suppressor of cytokine signaling 1 (SOCS1) limits NFkappaB signaling by decreasing p65 stability within the cell nucleus. FASEB J 25:863–874PubMedGoogle Scholar
  142. Takahashi R, Nishimoto S, Muto G, Sekiya T, Tamiya T, Kimura A, Morita R, Asakawa M, Chinen T, Yoshimura A (2011) SOCS1 is essential for regulatory T cell functions by preventing loss of Foxp3 expression as well as IFN-{gamma} and IL-17A production. J Exp Med 208:2055–2067PubMedPubMedCentralGoogle Scholar
  143. Takahashi R, Yoshimura A (2014) SOCS1 and regulation of regulatory T cells plasticity. J Immunol Res 2014:943149PubMedPubMedCentralGoogle Scholar
  144. Tanaka K, Ichiyama K, Hashimoto M, Yoshida H, Takimoto T, Takaesu G, Torisu T, Hanada T, Yasukawa H, Fukuyama S et al (2008) Loss of suppressor of cytokine signaling 1 in helper T cells leads to defective Th17 differentiation by enhancing antagonistic effects of IFN-gamma on STAT3 and Smads. J Immunol 180:3746–3756PubMedGoogle Scholar
  145. Trengove MC, Ward AC (2013) SOCS proteins in development and disease. Am J Clin Exp Immunol 2:1–29PubMedPubMedCentralGoogle Scholar
  146. Trop S, De Sepulveda P, Zuniga-Pflucker JC, Rottapel R (2001) Overexpression of suppressor of cytokine signaling-1 impairs pre-T-cell receptor-induced proliferation but not differentiation of immature thymocytes. Blood 97:2269–2277PubMedGoogle Scholar
  147. Tsukada J, Ozaki A, Hanada T, Chinen T, Abe R, Yoshimura A, Kubo M (2005) The role of suppressor of cytokine signaling 1 as a negative regulator for aberrant expansion of CD8alpha+ dendritic cell subset. Int Immunol 17:1167–1178PubMedGoogle Scholar
  148. Wang HY, Altman Y, Fang D, Elly C, Dai Y, Shao Y, Liu YC (2001) Cbl promotes ubiquitination of the T cell receptor zeta through an adaptor function of Zap-70. J Biol Chem 276:26004–26011PubMedGoogle Scholar
  149. Waskow C, Paul S, Haller C, Gassmann M, Rodewald HR (2002) Viable c-Kit(W/W) mutants reveal pivotal role for c-kit in the maintenance of lymphopoiesis. Immunity 17:277–288PubMedGoogle Scholar
  150. Wells AD, Walsh MC, Bluestone JA, Turka LA (2001) Signaling through CD28 and CTLA-4 controls two distinct forms of T cell anergy. J Clin Invest 108:895–903PubMedPubMedCentralGoogle Scholar
  151. Wormald S, Zhang JG, Krebs DL, Mielke LA, Silver J, Alexander WS, Speed TP, Nicola NA, Hilton DJ (2006) The comparative roles of suppressor of cytokine signaling-1 and -3 in the inhibition and desensitization of cytokine signaling. J Biol Chem 281:11135–11143PubMedGoogle Scholar
  152. Wu L, Liu YJ (2007) Development of dendritic-cell lineages. Immunity 26:741–750PubMedGoogle Scholar
  153. Yao R, Ma YL, Liang W, Li HH, Ma ZJ, Yu X, Liao YH (2012) MicroRNA-155 modulates Treg and Th17 cells differentiation and Th17 cell function by targeting SOCS1. PLoS ONE 7:e46082PubMedPubMedCentralGoogle Scholar
  154. Yasukawa H, Misawa H, Sakamoto H, Masuhara M, Sasaki A, Wakioka T, Ohtsuka S, Imaizumi T, Matsuda T, Ihle JN, Yoshimura A (1999) The JAK-binding protein JAB inhibits janus tyrosine kinase activity through binding in the activation loop. EMBO J 18:1309–1320PubMedPubMedCentralGoogle Scholar
  155. Yasukawa H, Ohishi M, Mori H, Murakami M, Chinen T, Aki D, Hanada T, Takeda K, Akira S, Hoshijima M et al (2003) IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages. Nat Immunol 4:551–556PubMedGoogle Scholar
  156. Yasukawa H, Sasaki A, Yoshimura A (2000) Negative regulation of cytokine signaling pathways. Annu Rev Immunol 18:143–164PubMedGoogle Scholar
  157. Yeganeh M, Gui Y, Kandhi R, Bobbala D, Tobelaim WS, Saucier C, Yoshimura A, Ferbeyre G, Ramanathan S, Ilangumaran S (2016) Suppressor of cytokine signaling 1-dependent regulation of the expression and oncogenic functions of p 21 in the liver. Oncog PMID:26725321Google Scholar
  158. Yoshida T, Ogata H, Kamio M, Joo A, Shiraishi H, Tokunaga Y, Sata M, Nagai H, Yoshimura A (2004) SOCS1 is a suppressor of liver fibrosis and hepatitis-induced carcinogenesis. J Exp Med 199:1701–1707PubMedPubMedCentralGoogle Scholar
  159. Yoshikawa H, Matsubara K, Qian GS, Jackson P, Groopman JD, Manning JE, Harris CC, Herman JG (2001) SOCS-1, a negative regulator of the JAK/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth- suppression activity. Nat Genet 28:29–35PubMedGoogle Scholar
  160. Yoshimura A (2013) CIS: the late-blooming eldest son. Nat Immunol 14:692–694PubMedGoogle Scholar
  161. Yoshimura A, Naka T, Kubo M (2007) SOCS proteins, cytokine signalling and immune regulation. Nat Rev Immunol 7:454–465PubMedGoogle Scholar
  162. Yoshimura A, Ohkubo T, Kiguchi T, Jenkins NA, Gilbert DJ, Copeland NG, Hara T, Miyajima A (1995) A novel cytokine-inducible gene CIS encodes an SH2-containing protein that binds to tyrosine-phosphorylated interleukin 3 and erythropoietin receptors. EMBO J 14:2816–2826PubMedPubMedCentralGoogle Scholar
  163. Yoshimura A, Yasukawa H (2012) JAK’s SOCS: a mechanism of inhibition. Immunity 36:157–159PubMedGoogle Scholar
  164. Yu Q, Park JH, Doan LL, Erman B, Feigenbaum L, Singer A (2006) Cytokine signal transduction is suppressed in preselection double-positive thymocytes and restored by positive selection. J Exp Med 203:165–175PubMedPubMedCentralGoogle Scholar
  165. Zeng R, Spolski R, Finkelstein SE, Oh S, Kovanen PE, Hinrichs CS, Pise-Masison CA, Radonovich MF, Brady JN, Restifo NP et al (2005) Synergy of IL-21 and IL-15 in regulating CD8 + T cell expansion and function. J Exp Med 201:139–148PubMedPubMedCentralGoogle Scholar
  166. Zhan Y, Davey GM, Graham KL, Kiu H, Dudek NL, Kay T, Lew AM (2009) SOCS1 negatively regulates the production of Foxp3 + CD4 + T cells in the thymus. Immunol Cell Biol 87:473–480PubMedGoogle Scholar
  167. Zhang JG, Metcalf D, Rakar S, Asimakis M, Greenhalgh CJ, Willson TA, Starr R, Nicholson SE, Carter W, Alexander WS et al (2001) The SOCS box of suppressor of cytokine signaling-1 is important for inhibition of cytokine action in vivo. Proc Natl Acad Sci USA 98:13261–13265PubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Subburaj Ilangumaran
    • 1
    Email author
  • Diwakar Bobbala
    • 1
  • Sheela Ramanathan
    • 1
  1. 1.Immunology Division, Faculty of Medicine and Health Sciences, Department of PediatricsUniversité de SherbrookeSherbrookeCanada

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