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Autoimmune Diseases
Volume 2013 (2013), Article ID 813256, 8 pages
http://dx.doi.org/10.1155/2013/813256
Review Article

Heat Shock Proteins and Regulatory T Cells

1School of Medical Science, Griffith Health Institute, Griffith University, Gold Coast, QLD, Australia
2National Centre for Neuroimmunology and Emerging Diseases, Griffith University, Gold Coast, QLD, Australia
3Queensland Health, Gold Coast Public Health Unit, Gold Coast, QLD, Australia
4Faculty of Health Science and Medicine, Bond University, Gold Coast, QLD, Australia

Received 2 July 2012; Revised 4 November 2012; Accepted 2 February 2013

Academic Editor: Kamal D. Moudgil

Copyright © 2013 E. W. Brenu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. B. Henderson, “Integrating the cell stress response: a new view of molecular chaperones as immunological and physiological homeostatic regulators,” Cell Biochemistry and Function, vol. 28, no. 1, pp. 1–14, 2010. View at Publisher · View at Google Scholar · View at Scopus
  2. H. H. Kampinga, J. Hageman, M. J. Vos et al., “Guidelines for the nomenclature of the human heat shock proteins,” Cell Stress and Chaperones, vol. 14, no. 1, pp. 105–111, 2009. View at Publisher · View at Google Scholar · View at Scopus
  3. C. Sarto, C. Valsecchi, F. Magni et al., “Expression of heat shock protein 27 in human renal cell carcinoma,” Proteomics, vol. 4, no. 8, pp. 2252–2260, 2004. View at Publisher · View at Google Scholar · View at Scopus
  4. G. Tomasello, C. Sciume, F. Rappa et al., “Hsp10, Hsp70, and Hsp90 immunohistochemical levels change in ulcerative colitis after therapy,” European Journal of Histochemistry, vol. 55, no. 4, article e38, 2011. View at Publisher · View at Google Scholar
  5. R. Rajaiah and K. D. Moudgil, “Heat-shock proteins can promote as well as regulate autoimmunity,” Autoimmunity Reviews, vol. 8, no. 5, pp. 388–393, 2009. View at Publisher · View at Google Scholar · View at Scopus
  6. Q. Pang, T. A. Christianson, W. Keeble, T. Koretsky, and G. C. Bagby, “The anti-apoptotic function of Hsp70 in the interferon-inducible double-stranded RNA-dependent protein kinase-mediated death signaling pathway requires the Fanconi anemia protein,” FANCC, vol. 277, pp. 49638–49643, 2002. View at Publisher · View at Google Scholar
  7. T. Gao and A. C. Newton, “The turn motif is a phosphorylation switch that regulates the binding of Hsp70 to protein kinase C,” Journal of Biological Chemistry, vol. 277, no. 35, pp. 31585–31592, 2002. View at Publisher · View at Google Scholar · View at Scopus
  8. A. L. Joly, G. Wettstein, G. Mignot, F. Ghiringhelli, and C. Garrido, “Dual role of heat shock proteins as regulators of apoptosis and innate immunity,” Journal of Innate Immunity, vol. 2, no. 3, pp. 238–247, 2010. View at Publisher · View at Google Scholar · View at Scopus
  9. S. K. Calderwood, S. S. Mambula, and P. J. Gray Jr., “Extracellular heat shock proteins in cell signaling and immunity,” Annals of the New York Academy of Sciences, vol. 1113, pp. 28–39, 2007. View at Publisher · View at Google Scholar · View at Scopus
  10. R. Schlecht, A. H. Erbse, B. Bukau, and M. P. Mayer, “Mechanics of Hsp70 chaperones enables differential interaction with client proteins,” Nature Structural and Molecular Biology, vol. 18, no. 3, pp. 345–351, 2011. View at Publisher · View at Google Scholar · View at Scopus
  11. S. Rüdiger, A. Buchberger, and B. Bukau, “Interaction of Hsp70 chaperones with substrates,” Nature Structural Biology, vol. 4, no. 5, pp. 342–349, 1997. View at Scopus
  12. A. Cegielska and C. Georgopoulos, “Functional domains of the Escherichia coli dnaK heat shock protein as revealed by mutational analysis,” Journal of Biological Chemistry, vol. 264, no. 35, pp. 21122–21130, 1989. View at Scopus
  13. C. Prodromou, S. M. Roe, R. O'Brien, J. E. Ladbury, P. W. Piper, and L. H. Pearl, “Identification and structural characterization of the ATP/ADP-binding site in the Hsp90 molecular chaperone,” Cell, vol. 90, no. 1, pp. 65–75, 1997. View at Publisher · View at Google Scholar · View at Scopus
  14. T. Gidalevitz, C. Biswas, H. Ding et al., “Identification of the N-terminal peptide binding site of glucose-regulated protein 94,” The Journal of Biological Chemistry, vol. 279, pp. 16543–16552, 2004.
  15. S. Vogen, T. Gidalevitz, C. Biswas et al., “Radicicol-sensitive peptide binding to the N-terminal portion of GRP94,” Journal of Biological Chemistry, vol. 277, no. 43, pp. 40742–40750, 2002. View at Publisher · View at Google Scholar · View at Scopus
  16. S. F. Harris, A. K. Shiau, and D. A. Agard, “The crystal structure of the carboxy-terminal dimerization domain of htpG, the Escherichia coli Hsp90, reveals a potential substrate binding site,” Structure, vol. 12, no. 6, pp. 1087–1097, 2004. View at Publisher · View at Google Scholar · View at Scopus
  17. J. Jiang, K. Prasad, E. M. Lafer, and R. Sousa, “Structural basis of interdomain communication in the Hsc70 chaperone,” Molecular Cell, vol. 20, no. 4, pp. 513–524, 2005. View at Publisher · View at Google Scholar · View at Scopus
  18. E. Schmitt, M. Gehrmann, M. Brunet, G. Multhoff, and C. Garrido, “Intracellular and extracellular functions of heat shock proteins: repercussions in cancer therapy,” Journal of Leukocyte Biology, vol. 81, no. 1, pp. 15–27, 2007. View at Publisher · View at Google Scholar · View at Scopus
  19. U. Banerji, M. Walton, F. Raynaud et al., “Pharmacokinetic-pharmacodynamic relationships for the heat shock protein 90 molecular chaperone inhibitor 17-allylamino, 17-demethoxygeldanamycin in human ovarian cancer xenograft models,” Clinical Cancer Research, vol. 11, no. 19, pp. 7023–7032, 2005. View at Publisher · View at Google Scholar · View at Scopus
  20. K. Nanbu, I. Konishi, M. Mandai et al., “Prognostic significance of heat shock proteins HSP70 and HSP90 in endometrial carcinomas,” Cancer Detection and Prevention, vol. 22, no. 6, pp. 549–555, 1998. View at Publisher · View at Google Scholar · View at Scopus
  21. P. Workman, “Combinatorial attack on multistep oncogenesis by inhibiting the Hsp90 molecular chaperone,” Cancer Letters, vol. 206, no. 2, pp. 149–157, 2004. View at Publisher · View at Google Scholar · View at Scopus
  22. A. Clayton, A. Turkes, H. Navabi, M. D. Mason, and Z. Tabi, “Induction of heat shock proteins in B-cell exosomes,” Journal of Cell Science, vol. 118, no. 16, pp. 3631–3638, 2005. View at Publisher · View at Google Scholar · View at Scopus
  23. I. Guzhova, K. Kislyakova, O. Moskaliova et al., “In vitro studies show that Hsp70 can be released by glia and that exogenous Hsp70 can enhance neuronal stress tolerance,” Brain Research, vol. 914, no. 1-2, pp. 66–73, 2001. View at Publisher · View at Google Scholar · View at Scopus
  24. C. Hunter-Lavin, E. L. Davies, M. M. F. V. G. Bacelar, M. J. Marshall, S. M. Andrew, and J. H. H. Williams, “Hsp70 release from peripheral blood mononuclear cells,” Biochemical and Biophysical Research Communications, vol. 324, no. 2, pp. 511–517, 2004. View at Publisher · View at Google Scholar · View at Scopus
  25. G. I. Lancaster and M. A. Febbraio, “Mechanisms of stress-induced cellular HSP72 release: implications for exercise-induced increases in extracellular HSP72,” Exercise immunology review., vol. 11, pp. 46–52, 2005. View at Scopus
  26. M. A. Bausero, R. Gastpar, G. Multhoff, and A. Asea, “Alternative mechanism by which IFN-γ enhances tumor recognition: active release of heat shock protein 72,” Journal of Immunology, vol. 175, no. 5, pp. 2900–2912, 2005. View at Scopus
  27. B. Dybdahl, S. A. Slørdahl, A. Waage, P. Kierulf, T. Espevik, and A. Sundan, “Myocardial ischaemia and the inflammatory response: release of heat shock protein 70 after myocardial infarction,” Heart, vol. 91, no. 3, pp. 299–304, 2005. View at Publisher · View at Google Scholar · View at Scopus
  28. F. U. Hartl and M. Hayer-Hartl, “Protein folding. Molecular chaperones in the cytosol: from nascent chain to folded protein,” Science, vol. 295, no. 5561, pp. 1852–1858, 2002. View at Publisher · View at Google Scholar · View at Scopus
  29. E. A. Craig, B. D. Gambill, and R. J. Nelson, “Heat shock proteins: molecular chaperones of protein biogenesis,” Microbiological Reviews, vol. 57, no. 2, pp. 402–414, 1993. View at Scopus
  30. S. Lindquist, “The heat-shock response,” Annual Review of Biochemistry, vol. 55, pp. 1151–1191, 1986. View at Publisher · View at Google Scholar
  31. C. Sõti, E. Nagy, Z. Giricz, L. Vígh, P. Csermely, and P. Ferdinandy, “Heat shock proteins as emerging therapeutic targets,” British Journal of Pharmacology, vol. 146, no. 6, pp. 769–780, 2005. View at Publisher · View at Google Scholar · View at Scopus
  32. K. D. Sarge, S. P. Murphy, and R. I. Morimoto, “Activation of heat shock gene transcription by heat shock factor 1 involves oligomerization, acquisition of DNA-binding activity, and nuclear localization and can occur in the absence of stress,” Molecular and Cellular Biology, vol. 13, no. 3, pp. 1392–1407, 1993. View at Scopus
  33. A. Gragerov and M. E. Gottesman, “Different peptide binding specificities of hsp70 family members,” Journal of Molecular Biology, vol. 241, no. 2, pp. 133–135, 1994. View at Publisher · View at Google Scholar · View at Scopus
  34. J. G. Facciponte, I. J. MacDonald, X. Y. Wang, H. Kim, M. H. Manjili, and J. R. Subjeck, “Heat shock proteins and scavenger receptors: role in adaptive immune responses,” Immunological Investigations, vol. 34, no. 3, pp. 325–342, 2005. View at Publisher · View at Google Scholar · View at Scopus
  35. U. Kumaraguru, C. D. Pack, and B. T. Rouse, “Toll-like receptor ligand links innate and adaptive immune responses by the production of heat-shock proteins,” Journal of Leukocyte Biology, vol. 73, no. 5, pp. 574–583, 2003. View at Publisher · View at Google Scholar · View at Scopus
  36. G. Multhoff, “Activation of natural killer cells by heat shock protein 70,” International Journal of Hyperthermia, vol. 25, no. 3, pp. 169–175, 2009. View at Publisher · View at Google Scholar · View at Scopus
  37. C. Gross, I. G. Schmidt-Wolf, S. Nagaraj et al., “Heat shock protein 70-reactivity is associated with increased cell surface density of CD94/CD56 on primary natural killer cells,” Cell Stress & Chaperones, vol. 8, pp. 348–360, 2003.
  38. S. Stangl, C. Gross, A. G. Pockley, A. A. Asea, and G. Multhoff, “Influence of Hsp70 and HLA-E on the killing of leukemic blasts by cytokine/Hsp70 peptide-activated human natural killer (NK) cells,” Cell Stress and Chaperones, vol. 13, no. 2, pp. 221–230, 2008. View at Publisher · View at Google Scholar · View at Scopus
  39. M. F. Tsan and B. Gao, “Heat shock proteins and immune system,” Journal of Leukocyte Biology, vol. 85, no. 6, pp. 905–910, 2009. View at Publisher · View at Google Scholar · View at Scopus
  40. W. Van Eden, R. Van Der Zee, and B. Prakken, “Heat-shock proteins induce T-cell regulation of chronic inflammation,” Nature Reviews Immunology, vol. 5, no. 4, pp. 318–330, 2005. View at Publisher · View at Google Scholar · View at Scopus
  41. W. Van Eden, G. Wick, S. Albani, and I. Cohen, “Stress, heat shock proteins, and autoimmunity: how immune responses to heat shock proteins are to be used for the control of chronic inflammatory diseases,” Annals of the New York Academy of Sciences, vol. 1113, pp. 217–237, 2007. View at Publisher · View at Google Scholar · View at Scopus
  42. J. M. van Noort, M. Bsibsi, P. Nacken, W. H. Gerritsen, and S. Amor, “The link between small heat shock proteins and the immune system,” The International Journal of Biochemistry & Cell Biology, vol. 44, no. 10, pp. 1670–1679, 2012. View at Publisher · View at Google Scholar
  43. Y. Bulut, K. S. Michelsen, L. Hayrapetian et al., “Mycobacterium tuberculosis heat shock proteins use diverse toll-like receptor pathways to activate pro-inflammatory signals,” Journal of Biological Chemistry, vol. 280, no. 22, pp. 20961–20967, 2005. View at Publisher · View at Google Scholar · View at Scopus
  44. J. S. H. Gaston, “Heat shock proteins as potential targets in the therapy of inflammatory arthritis,” Biotherapy, vol. 10, no. 3, pp. 197–203, 1998. View at Scopus
  45. P. A. MacAry, B. Javid, R. A. Floto et al., “HSP70 peptide binding mutants separate antigen delivery from dendritic cell stimulation,” Immunity, vol. 20, no. 1, pp. 95–106, 2004. View at Publisher · View at Google Scholar · View at Scopus
  46. S. Pawaria, M. N. Messmer, Y. J. Zhou, and R. J. Binder, “A role for the heat shock protein-CD91 axis in the initiation of immune responses to tumors,” Immunologic Research, vol. 50, pp. 255–260, 2011. View at Publisher · View at Google Scholar
  47. F. Stelter, “Structure/function relationships of CD14,” Chemical Immunology, vol. 74, pp. 25–41, 2000.
  48. A. Asea, S. K. Kraeft, E. A. Kurt-Jones et al., “HSP70 stimulates cytokine production through a CD 14-dependant pathway, demonstrating its dual role as a chaperone and cytokine,” Nature Medicine, vol. 6, no. 4, pp. 435–442, 2000. View at Publisher · View at Google Scholar · View at Scopus
  49. T. Kawai and S. Akira, “TLR signaling,” Cell Death & Differentiation, vol. 13, pp. 816–825, 2006. View at Publisher · View at Google Scholar
  50. T. S. Blackwell and J. W. Christman, “The role of nuclear factor-kappa B in cytokine gene regulation,” American Journal of Respiratory Cell and Molecular Biology, vol. 17, pp. 3–9, 1997.
  51. A. R. Brasier, “The NF-kappaB regulatory network,” Cardiovascular Toxicology, vol. 6, pp. 111–130, 2006. View at Publisher · View at Google Scholar
  52. D. Sun, D. Chen, B. Du, and J. Pan, “Heat shock response inhibits NF-kappaB activation and cytokine production in murine Kupffer cells,” The Journal of Surgical Research, vol. 129, pp. 114–121, 2005. View at Publisher · View at Google Scholar
  53. Y. Wang, C. Li, X. Wang, J. Zhang, and Z. Chang, “Heat shock response inhibits IL-18 expression through the JNK pathway in murine peritoneal macrophages,” Biochemical and Biophysical Research Communications, vol. 296, no. 3, pp. 742–748, 2002. View at Publisher · View at Google Scholar · View at Scopus
  54. S. K. Calderwood, S. S. Mambula, P. J. Gray Jr., and J. R. Theriault, “Extracellular heat shock proteins in cell signaling,” FEBS Letters, vol. 581, no. 19, pp. 3689–3694, 2007. View at Publisher · View at Google Scholar · View at Scopus
  55. M. Cohen-Sfady, G. Nussbaum, M. Pevsner-Fischer et al., “Heat shock protein 60 activates B cells via the TLR4-MyD88 pathway,” Journal of Immunology, vol. 175, pp. 3594–3602, 2005.
  56. A. Zanin-Zhorov, G. Nussbaum, S. Franitza, I. R. Cohen, and O. Lider, “T cells respond to heat shock protein 60 via TLR2: activation of adhesion and inhibition of chemokine receptors,” The FASEB Journal, vol. 17, no. 11, pp. 1567–1569, 2003. View at Scopus
  57. P. Matzinger, “The danger model: a renewed sense of self,” Science, vol. 296, no. 5566, pp. 301–305, 2002. View at Publisher · View at Google Scholar · View at Scopus
  58. W. van Eden, R. Spiering, F. Broere, and R. van der Zee, “A case of mistaken identity: HSPs are no DAMPs but DAMPERs,” Cell Stress & Chaperones, vol. 17, pp. 281–292, 2012.
  59. H. Kono and K. L. Rock, “How dying cells alert the immune system to danger,” Nature Reviews Immunology, vol. 8, no. 4, pp. 279–289, 2008. View at Publisher · View at Google Scholar · View at Scopus
  60. D. Tang, Y. Shi, L. Jang, K. Wang, W. Xiao, and X. Xiao, “Heat shock response inhibits release of high mobility group box 1 protein induced by endotoxin in murine macrophages,” Shock, vol. 23, no. 5, pp. 434–440, 2005. View at Publisher · View at Google Scholar · View at Scopus
  61. A. Hasegawa, H. Iwasaka, S. Hagiwara, and T. Noguchi, “Relationship between HMGB1 and tissue protective effects of HSP72 in a LPS-induced systemic inflammation model,” Journal of Surgical Research, vol. 169, no. 1, pp. 85–91, 2011. View at Publisher · View at Google Scholar · View at Scopus
  62. I. S. Singh, J. R. He, S. Calderwood, and J. D. Hasday, “A high affinity HSF-1 binding site in the 5′-untranslated region of the murine tumor necrosis factor-alpha gene is a transcriptional repressor,” The Journal of Biological Chemistry, vol. 277, pp. 4981–4988, 2002.
  63. W. van Eden, “Immunoregulation of autoimmune diseases,” Human Immunology, vol. 67, no. 6, pp. 446–453, 2006. View at Publisher · View at Google Scholar · View at Scopus
  64. W. Van Eden, F. Hauet-Broere, S. Berlo et al., “Stress proteins as inducers and targets of regulatory T cells in arthritis,” International Reviews of Immunology, vol. 24, no. 3-4, pp. 181–197, 2005. View at Publisher · View at Google Scholar · View at Scopus
  65. W. van Eden, U. Wendling, L. Paul, B. Prakken, P. van Kooten, and R. van der Zee, “Arthritis protective regulatory potential of self-heat shock protein cross-reactive T cells,” Cell Stress & Chaperones, vol. 5, pp. 452–457, 2000.
  66. Y. M. Snyder, L. Guthrie, G. F. Evans, and S. H. Zuckerman, “Transcriptional inhibition of endotoxin-induced monokine synthesis following heat shock in murine peritoneal macrophages,” Journal of Leukocyte Biology, vol. 51, no. 2, pp. 181–187, 1992. View at Scopus
  67. X. Z. Ding, C. M. Fernandez-Prada, A. K. Bhattacharjee, and D. L. Hoover, “Over-expression of hsp-70 inhibits bacterial lipopolysaccharide-induced production of cytokines in human monocyte-derived macrophages,” Cytokine, vol. 16, pp. 210–219, 2001. View at Publisher · View at Google Scholar
  68. B. Gao and M. F. Tsan, “Induction of cytokines by heat shock proteins and endotoxin in murine macrophages,” Biochemical and Biophysical Research Communications, vol. 317, no. 4, pp. 1149–1154, 2004. View at Publisher · View at Google Scholar · View at Scopus
  69. C. J. Workman, A. L. Szymczak-Workman, L. W. Collison, M. R. Pillai, and D. A. Vignali, “The development and function of regulatory T cells,” Cellular and Molecular Life Sciences, vol. 66, pp. 2603–2622, 2009.
  70. E. M. Shevach, “CD4+CD25+ suppressor T cells: more questions than answers,” Nature Reviews Immunology, vol. 2, no. 6, pp. 389–400, 2002. View at Scopus
  71. S. Sakaguchi, “Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self,” Nature Immunology, vol. 6, pp. 345–352, 2005.
  72. S. Sakaguchi, “Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses,” Annual Review of Immunology, vol. 22, pp. 531–562, 2004. View at Publisher · View at Google Scholar
  73. M. Yadav, C. Louvet, D. Davini et al., “Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo,” The Journal of Experimental Medicine, vol. 209, no. 10, pp. 1713–1722, 2012.
  74. S. Huang, L. Li, S. Liang, and W. Wang, “Conversion of peripheral CD4+CD25- T cells to CD4+CD25+ regulatory T cells by IFN-γ in patients with Guillain-Barré syndrome,” Journal of Neuroimmunology, vol. 217, no. 1-2, pp. 80–84, 2009. View at Publisher · View at Google Scholar · View at Scopus
  75. W. Chen, W. Jin, N. Hardegen et al., “Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3,” Journal of Experimental Medicine, vol. 198, no. 12, pp. 1875–1886, 2003. View at Publisher · View at Google Scholar · View at Scopus
  76. K. Kretschmer, I. Apostolou, D. Hawiger, K. Khazaie, M. C. Nussenzweig, and H. von Boehmer, “Inducing and expanding regulatory T cell populations by foreign antigen,” Nature Immunology, vol. 6, no. 12, pp. 1219–1227, 2005. View at Publisher · View at Google Scholar · View at Scopus
  77. M. H. Kaplan, Y. L. Sun, T. Hoey, and M. J. Grusby, “Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice,” Nature, vol. 382, pp. 174–177, 1996. View at Publisher · View at Google Scholar
  78. R. A. Seder, R. Gazzinelli, A. Sher, and W. E. Paul, “Interleukin 12 acts directly on CD4+ T cells to enhance priming for interferon γ production and diminishes interleukin 4 inhibition of such priming,” Proceedings of the National Academy of Sciences of the United States of America, vol. 90, no. 21, pp. 10188–10192, 1993. View at Publisher · View at Google Scholar · View at Scopus
  79. F. Cottrez and H. Groux, “Specialization in tolerance: innate CD4+CD25+ versus acquired Tr1 and Th3 regulatory T cells,” Transplantation, vol. 77, no. 1, Supplement, pp. S12–S15, 2004. View at Scopus
  80. A. Skapenko, J. R. Kalden, P. E. Lipsky, and H. Schulze-Koops, “The IL-4 receptor alpha-chain-binding cytokines, IL-4 and IL-13, induce forkhead box P3-expressing CD25+CD4+ regulatory T cells from CD25-CD4+ precursors,” Journal of Immunology, vol. 175, pp. 6107–6116, 2005.
  81. Y. Carrier, J. Yuan, V. K. Kuchroo, and H. L. Weiner, “Th3 cells in peripheral tolerance. I. Induction of Foxp3-positive regulatory T cells by Th3 cells derived from TGF-beta T cell-transgenic mice,” Journal of Immunology, vol. 178, pp. 179–185, 2007.
  82. E. Maggi, L. Cosmi, F. Liotta, P. Romagnani, S. Romagnani, and F. Annunziato, “Thymic regulatory T cells,” Autoimmunity Reviews, vol. 4, no. 8, pp. 579–586, 2005. View at Publisher · View at Google Scholar · View at Scopus
  83. L. S. Taams and A. N. Akbar, “Peripheral generation and function of CD4+CD25+ regulatory T cells,” Current Topics in Microbiology and Immunology, vol. 293, pp. 115–131, 2005. View at Scopus
  84. E. M. Shevach, “Mechanisms of foxp3+ T regulatory cell-mediated suppression,” Immunity, vol. 30, pp. 636–645, 2009.
  85. D. K. Sojka, Y. H. Huang, and D. J. Fowell, “Mechanisms of regulatory T-cell suppression—a diverse arsenal for a moving target,” Immunology, vol. 124, no. 1, pp. 13–22, 2008. View at Publisher · View at Google Scholar · View at Scopus
  86. G. S. Whitehead, R. H. Wilson, K. Nakano, L. H. Burch, H. Nakano, and D. N. Cook, “IL-35 production by inducible costimulator (ICOS)-positive regulatory T cells reverses established IL-17-dependent allergic airways disease,” Journal of Allergy and Clinical Immunology, vol. 129, pp. 207–215, 2012. View at Publisher · View at Google Scholar
  87. L. W. Collison, C. J. Workman, T. T. Kuo et al., “The inhibitory cytokine IL-35 contributes to regulatory T-cell function,” Nature, vol. 450, pp. 566–569, 2007. View at Publisher · View at Google Scholar
  88. S. Yamagiwa, J. D. Gray, S. Hashimoto, and D. A. Horwitz, “A role for TGF-β in the generation and expansion of CD4+CD25+ regulatory t cells from human peripheral blood,” Journal of Immunology, vol. 166, no. 12, pp. 7282–7289, 2001. View at Scopus
  89. M. Czystowska, L. Strauss, C. Bergmann, M. Szajnik, H. Rabinowich, and T. L. Whiteside, “Reciprocal granzyme/perforin-mediated death of human regulatory and responder T cells is regulated by interleukin-2 (IL-2),” Journal of Molecular Medicine, vol. 88, no. 6, pp. 577–588, 2010. View at Publisher · View at Google Scholar · View at Scopus
  90. X. Cao, S. F. Cai, T. A. Fehniger et al., “Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance,” Immunity, vol. 27, no. 4, pp. 635–646, 2007. View at Publisher · View at Google Scholar · View at Scopus
  91. M. Vaeth, T. Gogishvili, T. Bopp et al., “Regulatory T cells facilitate the nuclear accumulation of inducible cAMP early repressor (ICER) and suppress nuclear factor of activated T cell c1 (NFATc1),” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 6, pp. 2480–2485, 2011. View at Publisher · View at Google Scholar · View at Scopus
  92. X. Zhu, P. Yang, H. Zhou et al., “CD4+CD25+Tregs express an increased LAG-3 and CTLA-4 in anterior chamber-associated immune deviation,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 245, pp. 1549–1557, 2007. View at Publisher · View at Google Scholar
  93. H. Liu, M. Komai-Koma, D. Xu, and F. Y. Liew, “Toll-like receptor 2 signaling modulates the functions of CD4+ CD25+ regulatory T cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, pp. 7048–7053, 2006.
  94. A. Zanin-Zhorov, L. Cahalon, G. Tal, R. Margalit, O. Lider, and I. R. Cohen, “Heat shock protein 60 enhances CD4+CD25+ regulatory T cell function via innate TLR2 signaling,” Journal of Clinical Investigation, vol. 116, no. 7, pp. 2022–2032, 2006. View at Publisher · View at Google Scholar · View at Scopus
  95. M. Sakaguchi, H. Kitahara, T. Seto et al., “Surgery for acute type A aortic dissection in pregnant patients with Marfan syndrome,” European Journal of Cardio-thoracic Surgery, vol. 28, no. 2, pp. 280–283, 2005. View at Publisher · View at Google Scholar · View at Scopus
  96. J. A. Aalberse, B. Kapitein, S. de Roock et al., “Cord blood CD4+ T cells respond to self heat shock protein 60 (HSP60),” PloS One, vol. 6, article e24119, 2011.
  97. G. H. M. Van Puijvelde, T. Van Es, E. J. A. Van Wanrooij et al., “Induction of oral tolerance to HSP60 or an HSP60-peptide activates t cell regulation and reduces atherosclerosis,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 27, no. 12, pp. 2677–2683, 2007. View at Publisher · View at Google Scholar · View at Scopus
  98. H. Li, Y. Ding, G. Yi, Q. Zeng, and W. Yang, “Establishment of nasal tolerance to heat shock protein-60 alleviates atherosclerosis by inducing TGF-beta-dependent regulatory T cells,” Journal of Huazhong University of Science and Technology, vol. 32, pp. 24–30, 2012. View at Publisher · View at Google Scholar
  99. R. Sutmuller, A. Garritsen, and G. J. Adema, “Regulatory T cells and toll–like receptors: regulating the regulators,” Annals of the Rheumatic Diseases, vol. 66, Supplement 3, pp. iii91–iii95, 2007. View at Publisher · View at Google Scholar
  100. E. F. de Zoeten, L. Wang, K. Butler et al., “Histone deacetylase 6 and heat shock protein 90 control the functions of Foxp3(+) T-regulatory cells,” Molecular and Cellular Biology, vol. 31, pp. 2066–2078, 2011. View at Publisher · View at Google Scholar
  101. J. Dai, B. Liu, S. M. Ngoi, S. Sun, A. T. Vella, and Z. Li, “TLR4 hyperresponsiveness via cell surface expression of heat shock protein gp96 potentiates suppressive function of regulatory T cells,” Journal of Immunology, vol. 178, no. 5, pp. 3219–3225, 2007. View at Scopus
  102. I. Caramalho, T. Lopes-Carvalho, D. Ostler, S. Zelenay, M. Haury, and J. Demengeot, “Regulatory T cells selectively express toll-like receptors and are activated by lipopolysaccharide,” Journal of Experimental Medicine, vol. 197, no. 4, pp. 403–411, 2003. View at Publisher · View at Google Scholar · View at Scopus
  103. M. J. van Herwijnen, L. Wieten, R. van der Zee et al., “Regulatory T cells that recognize a ubiquitous stress-inducible self-antigen are long-lived suppressors of autoimmune arthritis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, pp. 14134–14139, 2012.
  104. L. Wieten, S. E. Berlo, C. B. T. Brink et al., “IL-10 is critically involved in mycobacterial HSP70 induced suppression of proteoglycan-induced arthritis,” PLoS ONE, vol. 4, no. 1, article e4186, Article ID e4186, 2009. View at Publisher · View at Google Scholar · View at Scopus
  105. T. J. Borges, B. N. Porto, C. A. Teixeira et al., “Prolonged survival of allografts induced by mycobacterial Hsp70 is dependent on CD4+CD25+ regulatory T cells,” PLoS ONE, vol. 5, no. 12, article e14264, Article ID e14264, 2010. View at Publisher · View at Google Scholar · View at Scopus
  106. M. Jaattela, D. Wissing, K. Kokholm, T. Kallunki, and M. Egeblad, “Hsp70 exerts its anti-apoptotic function downstream of caspase-3-like proteases,” The EMBO Journal, vol. 17, pp. 6124–6134, 1998. View at Publisher · View at Google Scholar
  107. J. C. Young, I. Moarefi, and F. U. Hartl, “Hsp90: a specialized but essential protein-folding tool,” Journal of Cell Biology, vol. 154, no. 2, pp. 267–273, 2001. View at Publisher · View at Google Scholar · View at Scopus
  108. S. Aoyagi and T. K. Archer, “Modulating molecular chaperone Hsp90 functions through reversible acetylation,” Trends in Cell Biology, vol. 15, no. 11, pp. 565–567, 2005. View at Publisher · View at Google Scholar · View at Scopus
  109. H. Zhang, Y. Xiao, Z. Zhu, B. Li, and M. I. Greene, “Immune regulation by histone deacetylases: a focus on the alteration of FOXP3 activity,” Immunology & Cell Biology, vol. 90, pp. 95–100, 2012. View at Publisher · View at Google Scholar
  110. R. Tao, E. F. De Zoeten, E. Ozkaynak et al., “Deacetylase inhibition promotes the generation and function of regulatory T cells,” Nature Medicine, vol. 13, no. 11, pp. 1299–1307, 2007. View at Publisher · View at Google Scholar · View at Scopus
  111. E. F. de Zoeten, L. Wang, H. Sai, W. H. Dillmann, and W. W. Hancock, “Inhibition of HDAC9 Increases T Regulatory Cell Function and Prevents Colitis in Mice,” Gastroenterology, vol. 138, no. 2, pp. 583–594, 2010. View at Publisher · View at Google Scholar · View at Scopus
  112. Y. Xiao, B. Li, Z. Zhou, W. W. Hancock, H. Zhang, and M. I. Greene, “Histone acetyltransferase mediated regulation of FOXP3 acetylation and Treg function,” Current Opinion in Immunology, vol. 22, no. 5, pp. 583–591, 2010. View at Publisher · View at Google Scholar · View at Scopus
  113. U. H. Beier, T. Akimova, Y. Liu, L. Wang, and W. W. Hancock, “Histone/protein deacetylases control Foxp3 expression and the heat shock response of T-regulatory cells,” Current Opinion in Immunology, vol. 23, pp. 670–678, 2011. View at Publisher · View at Google Scholar