Surveillance of antigen-presenting cells by CD4+CD25+ regulatory T cells in autoimmunity: Immunopathogenesis and therapeutic implications

American Journal of Pathology

Volumn 174, Issue 5, 2009, Pages 1575-1587

  André, Sébastien ^a,b,c   Tough, David F ^d   Lacroix Desmazes, Sébastien ^a,b,c   Kaveri, Srini V ^a,b,c   Bayry, Jagadeesh ^a,b,c  

^a INSERM   (France)

^b CENTRE DE RECHERCHE DES CORDELIERS   (France)

^c UNIVERSITÉ PARIS DESCARTES   (France)

^d GLAXOSMITHKLINE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

CD18 ANTIGEN; CD39 ANTIGEN; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; GRANZYME; INTERLEUKIN 10; INTERLEUKIN 1BETA; INTERLEUKIN 23; INTERLEUKIN 6; LYMPHOCYTE FUNCTION ASSOCIATED ANTIGEN 1; NEUROPILIN 1; PERFORIN; TRANSFORMING GROWTH FACTOR BETA; TUMOR NECROSIS FACTOR; INTERLEUKIN 2 RECEPTOR ALPHA;

ADAPTIVE IMMUNITY; ANTIGEN PRESENTING CELL; APOPTOSIS; AUTOIMMUNE DISEASE; AUTOIMMUNITY; CD4+ CD25+ T LYMPHOCYTE; HUMAN; IMMUNOLOGICAL TOLERANCE; IMMUNOPATHOGENESIS; IMMUNOREGULATION; IMMUNOTHERAPY; INNATE IMMUNITY; LYMPHOCYTE ACTIVATION; LYMPHOCYTE FUNCTION; NONHUMAN; PRIORITY JOURNAL; REVIEW; CD4+ T LYMPHOCYTE; IMMUNOLOGY; METABOLISM; PATHOLOGY; PHYSIOLOGY; REGULATORY T LYMPHOCYTE;

ANTIGEN-PRESENTING CELLS; AUTOIMMUNE DISEASES; AUTOIMMUNITY; CD4-POSITIVE T-LYMPHOCYTES; HUMANS; INTERLEUKIN-2 RECEPTOR ALPHA SUBUNIT; T-LYMPHOCYTES, REGULATORY;

EID: 65649133976     PISSN: 00029440     EISSN: 15252191     Source Type: Journal    
DOI: 10.2353/ajpath.2009.080987     Document Type: Review

References (120)

1. Sakaguchi S, Yamaguchi T, Nomura T, Ono M: Regulatory T cells and immune tolerance. Cell 2008, 133:775-787
2. Tang Q, Bluestone JA: The Foxp3+ regulatory T cell: a jack of all trades, master of regulation. Nat Immunol 2008, 9:239-244
3. Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, Kelly TE, Saulsbury FT, Chance PF, Ochs HD: The immune dysregulation, polyendocrinopathy, enteropathy X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 2001, 27:20-21 (Pubitemid 32044513)
4. Wildin RS, Ramsdell F, Peake J, Faravelli F, Casanova JL, Buist N, Levy-Lahad E, Mazzella M, Goulet O, Perroni L, Bricarelli FD, Byrne G, McEuen M, Proll S, Appleby M, Brunkow ME: X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet 2001, 27:18-20 (Pubitemid 32044512)
5. Hori S, Nomura T, Sakaguchi S: Control of regulatory T cell development by the transcription factor Foxp3. Science 2003, 299:1057-1061 (Pubitemid 36222930)
6. Fontenot JD, Gavin MA, Rudensky AY: Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003, 4:330-336
7. Khattri R, Cox T, Yasayko SA, Ramsdell F: An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol 2003, 4:337-342
8. Kim JM, Rasmussen JP, Rudensky AY: Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol 2007, 8:191-197 (Pubitemid 46152650)
9. Miyara M, Sakaguchi S: Natural regulatory T cells: mechanisms of suppression. Trends Mol Med 2007, 13:108-116 (Pubitemid 46341958)
10. Vignali DA, Collison LW, Workman CJ: How regulatory T cells work. Nat Rev Immunol 2008, 8:523-532
11. Steinman RM, Banchereau J: Taking dendritic cells into medicine. Nature 2007, 449:419-426 (Pubitemid 47509552)
12. Shortman K, Naik SH: Steady-state and inflammatory dendritic-cell development. Nat Rev Immunol 2007, 7:19-30 (Pubitemid 46020824)
13. Cederbom L, Hall H, Ivars F: CD4+CD25+ regulatory T cells down-regulate co-stimulatory molecules on antigen-presenting cells. Eur J Immunol 2000, 30:1538-1543 (Pubitemid 30342794)
14. Serra P, Amrani A, Yamanouchi J, Han B, Thiessen S, Utsugi T, Verdaguer J, Santamaria P: CD40 ligation releases immature dendritic cells from the control of regulatory CD4+CD25+ T cells. Immunity 2003, 19:877-889 (Pubitemid 37542307)
15. Fallarino F, Grohmann U, Hwang KW, Orabona C, Vacca C, Bianchi R, Belladonna ML, Fioretti MC, Alegre ML, Puccetti P: Modulation of tryptophan catabolism by regulatory T cells. Nat Immunol 2003, 4:1206-1212 (Pubitemid 37547898)
16. Misra N, Bayry J, Lacroix-Desmazes S, Kazatchkine MD, Kaveri SV: Cutting edge: human CD4+CD25+ T cells restrain the maturation and antigen-presenting function of dendritic cells. J Immunol 2004, 172:4676-4680 (Pubitemid 38456386)
17. Veldhoen M, Moncrieffe H, Hocking RJ, Atkins CJ, Stockinger B: Modulation of dendritic cell function by naive and regulatory CD4+ T cells. J Immunol 2006, 176:6202-6210
18. Tang Q, Adams JY, Tooley AJ, Bi M, Fife BT, Serra P, Santamaria P, Locksley RM, Krummel MF, Bluestone JA: Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice. Nat Immunol 2006, 7:83-92 (Pubitemid 41823872)
19. Tadokoro CE, Shakhar G, Shen S, Ding Y, Lino AC, Maraver A, Lafaille JJ, Dustin ML: Regulatory T cells inhibit stable contacts between CD4+ T cells and dendritic cells in vivo. J Exp Med 2006, 203:505-511
20. Houot R, Perrot I, Garcia E, Durand I, Lebecque S: Human CD4+CD25high regulatory T cells modulate myeloid but not plasmacytoid dendritic cells activation. J Immunol 2006, 176:5293-5298
21. Oderup C, Cederbom L, Makowska A, Cilio CM, Ivars F: Cytotoxic T lymphocyte antigen-4-dependent down-modulation of costimulatory molecules on dendritic cells in CD4+ CD25+ regulatory T-cell-mediated suppression. Immunology 2006, 118:240-249 (Pubitemid 43727429)
22. Bayry J, Triebel F, Kaveri SV, Tough DF: Human dendritic cells acquire a semimature phenotype and lymph node homing potential through interaction with CD4+CD25+ regulatory T cells. J Immunol 2007, 178:4184-4193 (Pubitemid 46492369)
23. Mahnke K, Ring S, Johnson TS, Schallenberg S, Schonfeld K, Storn V, Bedke T, Enk AH: Induction of immunosuppressive functions of dendritic cells in vivo by CD4+CD25+ regulatory T cells: role of B7-H3 expression and antigen presentation. Eur J Immunol 2007, 37:2117-2126 (Pubitemid 47250204)
24. Bayry J, Kaveri SV, Tough DF: Do activated human dendritic cells diminish the suppressive functions of CD4+, CD25+ regulatory T cells? Arthritis Rheum 2007, 56:3874-3876
25. Larmonier N, Marron M, Zeng Y, Cantrell J, Romanoski A, Sepassi M, Thompson S, Chen X, Andreansky S, Katsanis E: Tumor-derived CD4(+)CD25(+) regulatory T cell suppression of dendritic cell function involves TGF-β and IL-10. Cancer Immunol Immunother 2007, 56:48-59
26. Hanig J, Lutz MB: Suppression of mature dendritic cell function by regulatory T cells in vivo is abrogated by CD40 licensing. J Immunol 2008, 180:1405-1413
27. Bayry J, Tchilian EZ, Davies MN, Forbes EK, Draper SJ, Kaveri SV, Hill AV, Kazatchkine MD, Beverley PC, Flower DR, Tough DF: In silico identified CCR4 antagonists target regulatory T cells and exert adjuvant activity in vaccination. Proc Natl Acad Sci USA 2008, 105:10221-10226
28. Onishi Y, Fehervari Z, Yamaguchi T, Sakaguchi S: Foxp3+ natural regulatory T cells preferentially form aggregates on dendritic cells in vitro and actively inhibit their maturation. Proc Natl Acad Sci USA 2008, 105:10113-10118
29. Heit A, Gebhardt F, Lahl K, Neuenhahn M, Schmitz F, Anderl F, Wagner H, Sparwasser T, Busch DH, Kastenmuller K: Circumvention of regulatory CD4(+) T cell activity during cross-priming strongly enhances T cell-mediated immunity. Eur J Immunol 2008, 38:1585-1597
30. Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, Nomura T, Sakaguchi S: CTLA-4 control over Foxp3+ regulatory T cell function. Science 2008, 322:271-275
31. Oldenhove G, de Heusch M, Urbain-Vansanten G, Urbain J, Maliszewski C, Leo O, Moser M: CD4+ CD25+ regulatory T cells control T helper cell type 1 responses to foreign antigens induced by mature dendritic cells in vivo. J Exp Med 2003, 198:259-266 (Pubitemid 36987851)
32. Lewkowich IP, Herman NS, Schleifer KW, Dance MP, Chen BL, Dienger KM, Sproles AA, Shah JS, Kohl J, Belkaid Y, Wills-Karp M: CD4+CD25+ T cells protect against experimentally induced asthma and alter pulmonary dendritic cell phenotype and function. J Exp Med 2005, 202:1549-1561 (Pubitemid 41746601)
33. Strickland DH, Stumbles PA, Zosky GR, Subrata LS, Thomas JA, Turner DJ, Sly PD, Holt PG: Reversal of airway hyperresponsiveness by induction of airway mucosal CD4+CD25+ regulatory T cells. J Exp Med 2006, 203:2649-2660
34. Sarris M, Andersen KG, Randow F, Mayr L, Betz AG: Neuropilin-1 expression on regulatory T cells enhances their interactions with dendritic cells during antigen recognition. Immunity 2008, 28:402-413
35. Terme M, Chaput N, Combadiere B, Ma A, Ohteki T, Zitvogel L: Regulatory T cells control dendritic cell/NK cell cross-talk in lymph nodes at the steady state by inhibiting CD4+ self-reactive T cells. J Immunol 2008, 180:4679-4686
36. Giroux M, Yurchenko E, St-Pierre J, Piccirillo CA, Perreault C: T regulatory cells control numbers of NK cells and CD8α+ immature dendritic cells in the lymph node paracortex. J Immunol 2007, 179:4492-4502
37. Feunou P, Vanwetswinkel S, Gaudray F, Goldman M, Matthys P, Braun MY: Foxp3+CD25+ T regulatory cells stimulate IFN-γ-independent CD152-mediated activation of tryptophan catabolism that provides dendritic cells with immune regulatory activity in mice unresponsive to staphylococcal enterotoxin B. J Immunol 2007, 179:910-917
38. Grossman WJ, Verbsky JW, Barchet W, Colonna M, Atkinson JP, Ley TJ: Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity 2004, 21:589-601 (Pubitemid 39370513)
39. Liang B, Workman C, Lee J, Chew C, Dale BM, Colonna L, Flores M, Li N, Schweighoffer E, Greenberg S, Tybulewicz V, Vignali D, Clynes R: Regulatory T cells inhibit dendritic cells by lymphocyte activation gene-3 engagement of MHC class II. J Immunol 2008, 180:5916-5926
40. George JF, Braun A, Brusko TM, Joseph R, Bolisetty S, Wasserfall CH, Atkinson MA, Agarwal A, Kapturczak MH: Suppression by CD4+CD25+ regulatory T cells is dependent on expression of heme oxygenase-1 in antigen-presenting cells. Am J Pathol 2008, 173:154-160
41. Borsellino G, Kleinewietfeld M, Di Mitri D, Sternjak A, Diamantini A, Giometto R, Hopner S, Centonze D, Bernardi G, Dell'Acqua ML, Rossini PM, Battistini L, Rotzschke O, Falk K: Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood 2007, 110:1225-1232 (Pubitemid 47281420)
42. Suvas S, Kumaraguru U, Pack CD, Lee S, Rouse BT: CD4+CD25+ T cells regulate virus-specific primary and memory CD8+ T cell responses. J Exp Med 2003, 198:889-901
43. Easterbrook JD, Zink MC, Klein SL: Regulatory T cells enhance persistence of the zoonotic pathogen Seoul virus in its reservoir host. Proc Natl Acad Sci USA 2007, 104:15502-15507 (Pubitemid 47502946)
44. Pasare C, Medzhitov R: Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 2003, 299:1033-1036 (Pubitemid 36222922)
45. Mosser DM: The many faces of macrophage activation. J Leukoc Biol 2003, 73:209-212 (Pubitemid 36158295)
46. Ehrchen J, Steinmuller L, Barczyk K, Tenbrock K, Nacken W, Eisenacher M, Nordhues U, Sorg C, Sunderkotter C, Roth J: Glucocorticoids induce differentiation of a specifically activated, antiinflammatory subtype of human monocytes. Blood 2007, 109:1265-1274 (Pubitemid 46220679)
47. Weaver LK, Pioli PA, Wardwell K, Vogel SN, Guyre PM: Up-regulation of human monocyte CD163 upon activation of cell-surface Toll-like receptors. J Leukoc Biol 2007, 81:663-671 (Pubitemid 46393544)
48. Taams LS, van Amelsfort JM, Tiemessen MM, Jacobs KM, de Jong EC, Akbar AN, Bijlsma JW, Lafeber FP: Modulation of monocyte/macrophage function by human CD4+CD25+ regulatory T cells. Hum Immunol 2005, 66:222-230 (Pubitemid 40395242)
49. Mahajan D, Wang Y, Qin X, Zheng G, Wang YM, Alexander SI, Harris DC: CD4+CD25+ regulatory T cells protect against injury in an innate murine model of chronic kidney disease. J Am Soc Nephrol 2006, 17:2731-2741 (Pubitemid 44484663)
50. Tiemessen MM, Jagger AL, Evans HG, van Herwijnen MJ, John S, Taams LS: CD4+CD25+Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages. Proc Natl Acad Sci USA 2007, 104:19446-19451
51. Venet F, Pachot A, Debard AL, Bohe J, Bienvenu J, Lepape A, Powell WS, Monneret G: Human CD4+CD25+ regulatory T lymphocytes inhibit lipopolysaccharide-induced monocyte survival through a Fas/Fas ligand-dependent mechanism. J Immunol 2006, 177:6540-6547 (Pubitemid 44628873)
52. Maloy KJ, Salaun L, Cahill R, Dougan G, Saunders NJ, Powrie F: CD4+CD25+ T(R) cells suppress innate immune pathology through cytokine-dependent mechanisms. J Exp Med 2003, 197:111-119
53. Kryczek I, Wei S, Zou L, Zhu G, Mottram P, Xu H, Chen L, Zou W: Cutting edge: induction of B7-H4 on APCs through IL-10: novel suppressive mode for regulatory T cells. J Immunol 2006, 177:40-44 (Pubitemid 43939113)
54. LeBien TW, Tedder TF: B lymphocytes: how they develop and function. Blood 2008, 112:1570-1580
55. Zhao DM, Thornton AM, DiPaolo RJ, Shevach EM: Activated CD4+CD25+ T cells selectively kill B lymphocytes. Blood 2006, 107:3925-3932
56. Ludwig-Portugall I, Hamilton-Williams EE, Gottschalk C, Kurts C: Cutting Edge: cD25+ regulatory T cells prevent expansion and induce apoptosis of B cells specific for tissue autoantigens. J Immunol 2008, 181:4447-4451
57. Seo SJ, Fields ML, Buckler JL, Reed AJ, Mandik-Nayak L, Nish SA, Noelle RJ, Turka LA, Finkelman FD, Caton AJ, Erikson J: The impact of T helper and T regulatory cells on the regulation of anti-double-stranded DNA B cells. Immunity 2002, 16:535-546 (Pubitemid 34442578)
58. Bystry RS, Aluvihare V, Welch KA, Kallikourdis M, Betz AG: B cells and professional APCs recruit regulatory T cells via CCL4. Nat Immunol 2001, 2:1126-1132 (Pubitemid 33130146)
59. Lim HW, Hillsamer P, Kim CH: Regulatory T cells can migrate to follicles upon T cell activation and suppress GC-Th cells and GC-Th cell-driven B cell responses. J Clin Invest 2004, 114:1640-1649 (Pubitemid 40385555)
60. Eddahri F, Oldenhove G, Denanglaire S, Urbain J, Leo O, Andris F: CD4+ CD25+ regulatory T cells control the magnitude of T-dependent humoral immune responses to exogenous antigens. Eur J Immunol 2006, 36:855-863
61. Lim HW, Hillsamer P, Banham AH, Kim CH: Cutting edge: direct suppression of B cells by CD4+ CD25+ regulatory T cells. J Immunol 2005, 175:4180-4183
62. Nakamura K, Kitani A, Strober W: Cell contact-dependent immunosuppression by CD4(+)CD25(+) regulatory T cells is mediated by cell surface-bound transforming growth factor β. J Exp Med 2001, 194:629-644 (Pubitemid 32844773)
63. Herve M, Isnardi I, Ng YS, Bussel JB, Ochs HD, Cunningham-Rundles C, Meffre E: CD40 ligand and MHC class II expression are essential for human peripheral B cell tolerance. J Exp Med 2007, 204:1583-1593 (Pubitemid 47048025)
64. Fields ML, Hondowicz BD, Metzgar MH, Nish SA, Wharton GN, Picca CC, Caton AJ, Erikson J: CD4+ CD25+ regulatory T cells inhibit the maturation but not the initiation of an autoantibody response. J Immunol 2005, 175:4255-4264 (Pubitemid 41361959)
65. Ludewig B, Odermatt B, Landmann S, Hengartner H, Zinkernagel RM: Dendritic cells induce autoimmune diabetes and maintain disease via de novo formation of local lymphoid tissue. J Exp Med 1998, 188:1493-1501 (Pubitemid 28489586)
66. Boyman O, Conrad C, Tonel G, Gilliet M, Nestle FO: The pathogenic role of tissue-resident immune cells in psoriasis. Trends Immunol 2007, 28:51-57 (Pubitemid 46176734)
67. Blanco P, Palucka AK, Gill M, Pascual V, Banchereau J: Induction of dendritic cell differentiation by IFN-α in systemic lupus erythematosus. Science 2001, 294:1540-1543 (Pubitemid 33063928)
68. Page G, Lebecque S, Miossec P: Anatomic localization of immature and mature dendritic cells in an ectopic lymphoid organ: correlation with selective chemokine expression in rheumatoid synovium. J Immunol 2002, 168:5333-5341 (Pubitemid 34496002)
69. Hansen A, Lipsky PE, Dorner T: B-cell lymphoproliferation in chronic inflammatory rheumatic diseases. Nat Clin Pract Rheumatol 2007, 3:561-569 (Pubitemid 47514471)
70. Brusko TM, Putnam AL, Bluestone JA: Human regulatory T cells: role in autoimmune disease and therapeutic opportunities. Immunol Rev 2008, 223:371-390
71. Wang J, Ioan-Facsinay A, van der Voort EI, Huizinga TW, Toes RE: Transient expression of FOXP3 in human activated nonregulatory CD4+ T cells. Eur J Immunol 2007, 37:129-138 (Pubitemid 46128793)
72. Bayry J, Siberil S, Triebel F, Tough DF, Kaveri SV: Rescuing CD4+CD25+ regulatory T-cell functions in rheumatoid arthritis by cytokine-targeted monoclonal antibody therapy. Drug Discov Today 2007, 12:548-552 (Pubitemid 47039302)
73. Ehrenstein MR, Evans JG, Singh A, Moore S, Warnes G, Isenberg DA, Mauri C: Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFα therapy. J Exp Med 2004, 200:277-285 (Pubitemid 39031247)
74. Kriegel MA, Lohmann T, Gabler C, Blank N, Kalden JR, Lorenz HM: Defective suppressor function of human CD4+ CD25+ regulatory T cells in autoimmune polyglandular syndrome type II. J Exp Med 2004, 199:1285-1291 (Pubitemid 38620265)
75. Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA: Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med 2004, 199:971-979 (Pubitemid 38481088)
76. Balandina A, Lecart S, Dartevelle P, Saoudi A, Berrih-Aknin S: Functional defect of regulatory CD4(+)CD25+ T cells in the thymus of patients with autoimmune myasthenia gravis. Blood 2005, 105:735-741 (Pubitemid 40070760)
77. Lindley S, Dayan CM, Bishop A, Roep BO, Peakman M, Tree TI: Defective suppressor function in CD4(+)CD25(+) T-cells from patients with type 1 diabetes. Diabetes 2005, 54:92-99 (Pubitemid 40105099)
78. Valencia X, Stephens G, Goldbach-Mansky R, Wilson M, Shevach EM, Lipsky PE: TNF downmodulates the function of human CD4+CD25hi T-regulatory cells. Blood 2006, 108:253-261
79. Nadkarni S, Mauri C, Ehrenstein MR: Anti-TNF-alpha therapy induces a distinct regulatory T cell population in patients with rheumatoid arthritis via TGF-beta. J Exp Med 2007, 204:33-39 (Pubitemid 46148753)
80. Valencia X, Yarboro C, Illei G, Lipsky PE: Deficient CD4+CD25high T regulatory cell function in patients with active systemic lupus erythematosus. J Immunol 2007, 178:2579-2588 (Pubitemid 46233461)
81. Yu J, Heck S, Patel V, Levan J, Yu Y, Bussel JB, Yazdanbakhsh K: Defective circulating CD25 regulatory T cells in patients with chronic immune thrombocytopenic purpura. Blood 2008, 112:1325-1328
82. Venigalla RK, Tretter T, Krienke S, Max R, Eckstein V, Blank N, Fiehn C, Ho AD, Lorenz HM: Reduced CD4+, CD25- T cell sensitivity to the suppressive function of CD4+, CD25high, CD127-/low regulatory T cells in patients with active systemic lupus erythematosus. Arthritis Rheum 2008, 58:2120-2130
83. Valencia X, Lipsky PE: CD4+CD25+FoxP3+ regulatory T cells in autoimmune diseases. Nat Clin Pract Rheumatol 2007, 3:619-626
84. Zozulya AL, Wiendl H: The role of regulatory T cells in multiple sclerosis. Nat Clin Pract Neurol 2008, 4:384-398
85. Pasare C, Medzhitov R: Toll-dependent control mechanisms of CD4 T cell activation. Immunity 2004, 21:733-741 (Pubitemid 39487894)
86. King IL, Segal BM: Cutting edge: iL-12 induces CD4+CD25- T cell activation in the presence of T regulatory cells. J Immunol 2005, 175:641-645 (Pubitemid 41094943)
87. O'Sullivan BJ, Thomas HE, Pai S, Santamaria P, Iwakura Y, Steptoe RJ, Kay TW, Thomas R: IL-1β breaks tolerance through expansion of CD25+ effector T cells. J Immunol 2006, 176:7278-7287 (Pubitemid 43849028)
88. Wan S, Xia C, Morel L: IL-6 produced by dendritic cells from lupus-prone mice inhibits CD4+CD25+ T cell regulatory functions. J Immunol 2007, 178:271-279 (Pubitemid 46033610)
89. Bettelli E, Korn T, Oukka M, Kuchroo VK: Induction and effector functions of T(H)17 cells. Nature 2008, 453:1051-1057
90. Deleuran B, Abraham DJ: Possible implication of the effector CD4+ T-cell subpopulation TH17 in the pathogenesis of systemic scleroderma. Nat Clin Pract Rheumatol 2007, 3:682-683 (Pubitemid 350187010)
91. Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F: Interleukins 1β and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol 2007, 8:942-949 (Pubitemid 47300008)
92. Wilson NJ, Boniface K, Chan JR, McKenzie BS, Blumenschein WM, Mattson JD, Basham B, Smith K, Chen T, Morel F, Lecron JC, Kastelein RA, Cua DJ, McClanahan TK, Bowman EP, de Waal Malefyt R: Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol 2007, 8:950-957 (Pubitemid 47300009)
93. Chen Z, Tato CM, Muul L, Laurence A, O'Shea JJ: Distinct regulation of interleukin-17 in human T helper lymphocytes. Arthritis Rheum 2007, 56:2936-2946 (Pubitemid 47502740)
94. Yang L, Anderson DE, Baecher-Allan C, Hastings WD, Bettelli E, Oukka M, Kuchroo VK, Hafler DA: IL-21 and TGF-β are required for differentiation of human T(H)17 cells. Nature 2008, 454:350-352
95. Manel N, Unutmaz D, Littman DR: The differentiation of human T(H)-17 cells requires transforming growth factor-β and induction of the nuclear receptor RORγt. Nat Immunol 2008, 9:641-649
96. Monteleone G, Pallone F, MacDonald TT: Interleukin-21: a critical regulator of the balance between effector and regulatory T-cell responses. Trends Immunol 2008, 29:290-294
97. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK: Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006, 441:235-238
98. Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B: TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 2006, 24:179-189 (Pubitemid 43214587)
99. Bettelli E, Korn T, Kuchroo VK: Th17: the third member of the effector T cell trilogy. Curr Opin Immunol 2007, 19:652-657 (Pubitemid 350236805)
100. Zhou L, Ivanov II, Spolski R, Min R, Shenderov K, Egawa T, Levy DE, Leonard WJ, Littman DR: IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol 2007, 8:967-974 (Pubitemid 47300011)
101. Korn T, Bettelli E, Gao W, Awasthi A, Jager A, Strom TB, Oukka M, Kuchroo VK: IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 2007, 448:484-487 (Pubitemid 47123515)
102. Samanta A, Li B, Song X, Bembas K, Zhang G, Katsumata M, Saouaf SJ, Wang Q, Hancock WW, Shen Y, Greene MI: TGF-β and IL-6 signals modulate chromatin binding and promoter occupancy by acetylated FOXP3. Proc Natl Acad Sci USA 2008, 105:14023-14027
103. Bayry J, Lacroix-Desmazes S, Kazatchkine MD, Kaveri SV: Monoclonal antibody and intravenous immunoglobulin therapy for rheumatic diseases: rationale and mechanisms of action. Nat Clin Pract Rheumatol 2007, 3:262-272 (Pubitemid 46711473)
104. Ulfgren AK, Andersson U, Engstrom M, Klareskog L, Maini RN, Taylor PC: Systemic anti-tumor necrosis factor α therapy in rheumatoid arthritis down-regulates synovial tumor necrosis factor α synthesis. Arthritis Rheum 2000, 43:2391-2396
105. Toichi E, Torres G, McCormick TS, Chang T, Mascelli MA, Kauffman CL, Aria N, Gottlieb AB, Everitt DE, Frederick B, Pendley CE, Cooper KD: An anti-IL-12p40 antibody down-regulates type 1 cytokines, chemokines, and IL-12/IL-23 in psoriasis. J Immunol 2006, 177:4917-4926 (Pubitemid 44469828)
106. Krueger GG, Langley RG, Leonardi C, Yeilding N, Guzzo C, Wang Y, Dooley LT, Lebwohl M: A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N Engl J Med 2007, 356:580-592 (Pubitemid 46220818)
107. Saadoun D, Rosenzwajg M, Landau D, Piette JC, Klatzmann D, Cacoub P: Restoration of peripheral immune homeostasis after rituximab in mixed cryoglobulinemia vasculitis. Blood 2008, 111:5334-5341
108. Vallerskog T, Gunnarsson I, Widhe M, Risselada A, Klareskog L, van Vollenhoven R, Malmstrom V, Trollmo C: Treatment with rituximab affects both the cellular and the humoral arm of the immune system in patients with SLE. Clin Immunol 2007, 122:62-74 (Pubitemid 46026695)
109. Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB: NF-κB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature 1999, 401:82-85 (Pubitemid 29418447)
110. Bensinger SJ, Walsh PT, Zhang J, Carroll M, Parsons R, Rathmell JC, Thompson CB, Burchill MA, Farrar MA, Turka LA: Distinct IL-2 receptor signaling pattern in CD4+CD25+ regulatory T cells. J Immunol 2004, 172:5287-5296
111. Crellin NK, Garcia RV, Levings MK: Altered activation of AKT is required for the suppressive function of human CD4+CD25+ T regulatory cells. Blood 2007, 109:2014-2022 (Pubitemid 46348201)
112. Camps M, Ruckle T, Ji H, Ardissone V, Rintelen F, Shaw J, Ferrandi C, Chabert C, Gillieron C, Francon B, Martin T, Gretener D, Perrin D, Leroy D, Vitte PA, Hirsch E, Wymann MP, Cirillo R, Schwarz MK, Rommel C: Blockade of PI3Kγ suppresses joint inflammation and damage in mouse models of rheumatoid arthritis. Nat Med 2005, 11:936-943 (Pubitemid 41294438)
113. Di Cristofano A, Kotsi P, Peng YF, Cordon-Cardo C, Elkon KB, Pandolfi PP: Impaired Fas response and autoimmunity in Pten+/- mice. Science 1999, 285:2122-2125 (Pubitemid 29451429)
114. Ivashkiv LB, Hu X: The JAK/STAT pathway in rheumatoid arthritis: pathogenic or protective? Arthritis Rheum 2003, 48:2092-2096
115. Tarner IH, Muller-Ladner U, Gay S: Emerging targets of biologic therapies for rheumatoid arthritis. Nat Clin Pract Rheumatol 2007, 3:336-345 (Pubitemid 46864888)
116. Mbalaviele G, Anderson G, Jones A, De Ciechi P, Settle S, Mnich S, Thiede M, Abu-Am Y, Portanova J, Monahan J: Inhibition of p38 mitogen-activated protein kinase prevents inflammatory bone destruction. J Pharmacol Exp Ther 2006, 317:1044-1053 (Pubitemid 43764107)
117. Medicherla S, Ma JY, Mangadu R, Jiang Y, Zhao JJ, Almirez R, Kerr I, Stebbins EG, O'Young G, Kapoun AM, Luedtke G, Chakravarty S, Dugar S, Genant HK, Protter AA: A selective p38α mitogen-activated protein kinase inhibitor reverses cartilage and bone destruction in mice with collagen-induced arthritis. J Pharmacol Exp Ther 2006, 318:132-141 (Pubitemid 43920750)
118. Sun SC, Ley SC: New insights into NF-κB regulation and function. Trends Immunol 2008, 29:469-478
119. McIntyre KW, Shuster DJ, Gillooly KM, Dambach DM, Pattoli MA, Lu P, Zhou XD, Qiu Y, Zusi FC, Burke JR: A highly selective inhibitor of IκB kinase. BMS-345541, blocks both joint inflammation and destruction in collagen-induced arthritis in mice. Arthritis Rheum 2003, 48:2652-2659
120. Roncarolo M-G, Battaglia M: Regulatory T-cell immunotherapy for tolerance to self antigens and alloantigens in humans. Nat Rev Immunol 2007, 7:585-598 (Pubitemid 47123554)