TGF-β: A mobile purveyor of immune privilege

Immunological Reviews

Volumn 213, Issue 1, 2006, Pages 213-227

  Wahl, Sharon M ^a   Wen, Jie ^a   Moutsopoulos, Niki ^a  

^a NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH   (United States)

Author keywords

Immune privilege; Immune surveillance; Macrophages; TGF ; Tolerance; Tumor

Indexed keywords

ANTIGEN; CD4 ANTIGEN; CD8 ANTIGEN; INTERLEUKIN 2 RECEPTOR ALPHA; POLYPEPTIDE; TRANSCRIPTION FACTOR FOXP3; TRANSFORMING GROWTH FACTOR BETA; TUMOR ANTIGEN;

ANTIGEN RECOGNITION; BONE MARROW CELL; CANCER INFILTRATION; CARCINOGENESIS; CD4+ CD25+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL DIFFERENTIATION; CELL SECRETION; CELLULAR IMMUNITY; CYTOKINE RELEASE; DENDRITIC CELL; EFFECTOR CELL; HELPER CELL; HOMEOSTASIS; HOST RESISTANCE; HUMAN; IMMUNE DEFICIENCY; IMMUNE RESPONSE; IMMUNOCOMPETENT CELL; IMMUNOLOGICAL TOLERANCE; IMMUNOREGULATION; IMMUNOSURVEILLANCE; INNATE IMMUNITY; LYMPHOCYTE DIFFERENTIATION; MACROPHAGE; MEDIATOR; MONOCYTE; NATURAL KILLER CELL; NONHUMAN; PRIORITY JOURNAL; PROTEIN TRANSPORT; REGULATORY T LYMPHOCYTE; REVIEW; T LYMPHOCYTE; TH1 CELL; TH2 CELL; TUMOR IMMUNOLOGY;

ANIMALS; HUMANS; IMMUNE SYSTEM; IMMUNE TOLERANCE; NEOPLASMS; TRANSFORMING GROWTH FACTOR BETA;

EID: 33748756028     PISSN: 01052896     EISSN: 1600065X     Source Type: Journal    
DOI: 10.1111/j.1600-065X.2006.00437.x     Document Type: Review

References (199)

1. Medawar P. Immunity to homologous grafted skin. III. The fate of skin homografts transplanted to the brain, to subcutaneous tissue and to the anterior chamber of the eye. J Exp Pathol 1948;29:58.
2. Streilein JW. Tissue barriers, immunosuppressive microenvironments, and privileged sites: the eye's point of view. Reg Immunol 1993;5:253-268.
3. Pollack IF, Lund RD. The blood-brain barrier protects foreign antigens in the brain from immune attack. Exp Neurol 1990;108:114-121.
4. Head JR, Billingham RE. Immune privilege in the testis. II. Evaluation of potential local factors. Transplantation 1985;40:269-275.
5. Spitalny GL, North RJ. Subversion of host defense mechanisms by malignant tumors: an established tumor as a privileged site for bacterial growth. J Exp Med 1977;145:1264-1277.
6. Ferguson TA, Green DR, Griffith TS. Cell death and immune privilege. Int Rev Immunol 2002;21:153-172.
7. Chen PW, Ksander BR. Immune privilege, tumors and the eye. In: Streilein JW, ed. Immune Response and the Eye. Basel: Karger, 1999:137-154.
8. Mesa C, Fernandez LE. Challenges facing adjuvants for cancer immunotherapy. Immunol Cell Biol 2004;82:644-650.
9. Wakefield LM, Roberts AB. TGF-beta signaling: positive and negative effects on tumorigenesis. Curr Opin Genet Dev 2002;12:22-29.
10. de Visser KE, Eichten A, Coussens LM. Paradoxical roles of the immune system during cancer development. Nat Rev Cancer 2006;6:24-37.
11. Niederkorn JY. See no evil, hear no evil, do no evil: the lessons of immune privilege. Nat Immunol 2006;7:354-359.
12. Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA. Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol 2006;24:99-146.
13. Wahl SM, Chen W. Transforming growth factor-beta-induced regulatory T cells referee inflammatory and autoimmune diseases. Arthritis Res Ther 2005;7:62-68.
14. Wahl SM, Chen W. TGF-beta: how tolerant can it be? Immunol Res 2003;28:167-179.
15. Chen W, Wahl SM. TGF-beta: the missing link in CD4+CD25+ regulatory T cell-mediated immunosuppression. Cytokine Growth Factor Rev 2003;14:85-89.
16. Wahl SM. Transforming growth factor beta (TGF-beta) in inflammation: a cause and a cure. J Clin Immunol 1992;12:61-74.
17. Wahl SM, McCartney-Francis N, Mergenhagen SE. Inflammatory and immunomodulatory roles of TGF-beta. Immunol Today 1989;10:258-261.
18. Shi Y, Massague J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 2003;113:685-700.
19. Derynck R, Akhurst RJ, Balmain A. TGF-beta signaling in tumor suppression and cancer progression. Nat Genet 2001;29:117-129.
20. McCartney-Francis N, Wahl SM. Transforming growth factor-beta at the crossroads between inflammation, suppression and cancer. In: Teicher B, ed. Methods in Molecular Biology. Totowa: Humana Press, 2006 (in press).
21. Khalil N. TGF-beta: from latent to active. Microbes Infect 1999;1:1255-1263.
22. Mehra A, Wrana JL. TGF-beta and the Smad signal transduction pathway. Biochem Cell Biol 2002;80:605-622.
23. Massague J. TGFbeta signaling: receptors, transducers, and Mad proteins. Cell 1996;85:947-950.
24. de Caestecker M. The transforming growth factor-beta superfamily of receptors. Cytokine Growth Factor Rev 2004;15:1-11.
25. Attisano L, Tuen Lee-Hoeflich S. The Smads. Genome Biol 2001;2:Reviews3010.
26. Moustakas A, Souchelnytskyi S, Heldin CH. Smad regulation in TGF-beta signal transduction. J Cell Sci 2001;114:4359-4369.
27. Fink SP, et al. Transforming growth factor-beta-induced growth inhibition in a Smad4 mutant colon adenoma cell line. Cancer Res 2001;61:256-260.
28. de Caestecker MP, Hemmati P, Larisch-Bloch S, Ajmera R, Roberts AB, Lechleider RJ. Characterization of functional domains within Smad4/DPC4. J Biol Chem 1997;272:13690-13696.
29. Massague J, Blain SW, Lo RS. TGFbeta signaling in growth control, cancer, and heritable disorders. Cell 2000;103:295-309.
30. Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 2003;425:577-584.
31. Moustakas A, Heldin CH. Non-Smad TGF-beta signals. J Cell Sci 2005;118:3573-3584.
32. Ten Dijke P, Goumans MJ, Itoh F, Itoh S. Regulation of cell proliferation by Smad proteins. J Cell Physiol 2002;191:1-16.
33. Park SH. Fine tuning and cross-talking of TGF-beta signal by inhibitory Smads. J Biochem Mol Biol 2005;38:9-16.
34. Blobe GC, Liu X, Fang SJ, How T, Lodish HF. A novel mechanism for regulating transforming growth factor beta (TGF-beta) signaling. Functional modulation of type III TGF-beta receptor expression through interaction with the PDZ domain protein, GIPC. J Biol Chem 2001;276:39608-39617.
35. Kulkarni AB, Thyagarajan T, Letterio JJ. Function of cytokines within the TGF-beta superfamily as determined from transgenic and gene knockout studies in mice. Curr Mol Med 2002;2:303-327.
36. Ashcroft GS, et al. Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response. Nat Cell Biol 1999;1:260-266.
37. Gorelik L, Flavell RA. Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity 2000;12:171-181.
38. Wahl SM, et al. Transforming growth factor type beta induces monocyte chemotaxis and growth factor production. Proc Natl Acad Sci USA 1987;84:5788-5792.
39. Gorham JD, Guler ML, Fenoglio D, Gubler U, Murphy KM. Low dose TGF-beta attenuates IL-12 responsiveness in murine Th cells. J Immunol 1998;161:1664-1670.
40. Gorelik L, Constant S, Flavell RA. Mechanism of transforming growth factor beta-induced inhibition of T helper type 1 differentiation. J Exp Med 2002;195:1499-1505.
41. Gorelik L, Fields PE, Flavell RA. Cutting edge: TGF-beta inhibits Th type 2 development through inhibition of GATA-3 expression. J Immunol 2000;165:4773-4777.
42. Heath VL, Murphy EE, Crain C, Tomlinson MG, O'Garra A. TGF-beta1 down-regulates Th2 development and results in decreased IL-4-induced STAT6 activation and GATA-3 expression. Eur J Immunol 2000;30:2639-2649.
43. Wahl SM, Vazquez N, Chen W. Regulatory T cells and transcription factors: gatekeepers in allergic inflammation. Curr Opin Immunol 2004;16:768-774.
44. Tato CM, Laurence A, O'Shea JJ. Helper T cell differentiation enters a new era: le roi est mort; vive le Roi! J Exp Med 2006;203:809-812.
45. Mangan PR, et al. TGF-beta induces development of the TH17 lineage. Nature 2006;441:231-234.
46. Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 2006;24:179-189.
47. Kulkarni AB, et al. Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci USA 1993;90:770-774.
48. Diebold RJ, et al. Early-onset multifocal inflammation in the transforming growth factor beta 1-null mouse is lymphocyte mediated. Proc Natl Acad Sci USA 1995;92:12215-12219.
49. Christ M, et al. Immune dysregulation in TGF-beta 1-deficient mice. J Immunol 1994;153:1936-1946.
50. Chen W, et al. Requirement for transforming growth factor beta1 in controlling T cell apoptosis. J Exp Med 2001;194:439-453.
51. Shull MM, et al. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 1992;359:693-699.
52. Lucas PJ, Kim SJ, Melby SJ, Gress RE. Disruption of T cell homeostasis in mice expressing a T cell-specific dominant negative transforming growth factor beta II receptor. J Exp Med 2000;191:1187-1196.
53. De Wever O, Mareel M. Role of tissue stroma in cancer cell invasion. J Pathol 2003;200:429-447.
54. Elliott RL, Blobe GC. Role of transforming growth factor Beta in human cancer. J Clin Oncol 2005;23:2078-2093.
55. Qiu W, Schonleben F, Li X, Su GH. Disruption of transforming growth factor beta-Smad signaling pathway in head and neck squamous cell carcinoma as evidenced by mutations of SMAD2 and SMAD4. Cancer Lett 2006; (in press).
56. Narayan S, Thangasamy T, Balusu R. Transforming growth factor -beta receptor signaling in cancer. Front Biosci 2005;10:1135-1145.
57. Lin SY, Elledge SJ. Multiple tumor suppressor pathways negatively regulate telomerase. Cell 2003;113:881-889.
58. Wick W, Naumann U, Weller M. Transforming growth factor-beta: a molecular target for the future therapy of glioblastoma. Curr Pharm Des 2006;12:341-349.
59. Brandes ME, Mai UE, Ohura K, Wahl SM. Type I transforming growth factor-beta receptors on neutrophils mediate chemotaxis to transforming growth factor-beta. J Immunol 1991;147:1600-1606.
60. Maghazachi AA, al-Aoukaty A. Transforming growth factor-beta 1 is chemotactic for interleukin-2-activated natural killer cells. Nat Immunol 1993;12:57-65.
61. Wahl SM, Swisher J, McCartney-Francis N, Chen W. TGF-beta: the perpetrator of immune suppression by regulatory T cells and suicidal T cells. J Leukoc Biol 2004;76:15-24.
62. Balkwill F, Charles KA, Mantovani A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 2005;7:211-217.
63. Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 2004;4:71-78.
64. Makitie T, Summanen P, Tarkkanen A, Kivela T. Tumor-infiltrating macrophages (CD68(+) cells) and prognosis in malignant uveal melanoma. Invest Ophthalmol Vis Sci 2001;42:1414-1421.
65. Leek RD, Landers RJ, Harris AL, Lewis CE. Necrosis correlates with high vascular density and focal macrophage infiltration in invasive carcinoma of the breast. Br J Cancer 1999;79:991-995.
66. Leek RD, Lewis CE, Whitehouse R, Greenall M, Clarke J, Harris AL. Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res 1996;56:4625-4629.
67. Chen JJ, et al. Tumor-associated macrophages: the double-edged sword in cancer progression. J Clin Oncol 2005;23:953-964.
68. Balkwill F, Coussens LM. Cancer: an inflammatory link. Nature 2004;431:405-406.
69. Clevers H. At the crossroads of inflammation and cancer. Cell 2004;118:671-674.
70. Wahl SM. Transforming growth factor beta: the good, the bad, and the ugly. J Exp Med 1994;180:1587-1590.
71. Chen W, Frank ME, Jin W, Wahl SM. TGF-beta released by apoptotic T cells contributes to an immunosuppressive milieu. Immunity 2001;14:715-725.
72. Fadok VA, Bratton DL, Henson PM. Phagocyte receptors for apoptotic cells: recognition, uptake, and consequences. J Clin Invest 2001;108:957-962.
73. Kim R, Emi M, Tanabe K. Cancer cell immune escape and tumor progression by exploitation of anti-inflammatory and proinflammatory responses. Cancer Biol Ther 2005;4:924-933.
74. Igney FH, Krammer PH. Tumor counterattack: fact or fiction? Cancer Immunol Immunother 2005;54:1127-1136.
75. Kuijlen JM, et al. TRAIL-receptor expression is an independent prognostic factor for survival in patients with a primary glioblastoma multiforme. J Neurooncol 2006;78:31-39.
76. Wilbanks GA, Streilein JW. Fluids from immune privileged sites endow macrophages with the capacity to induce antigen-specific immune deviation via a mechanism involving transforming growth factor-beta. Eur J Immunol 1992;22:1031-1036.
77. Kelsall BL, Leon F. Involvement of intestinal dendritic cells in oral tolerance, immunity to pathogens, and inflammatory bowel disease. Immunol Rev 2005;206:132-148.
78. Larmonier N, et al. Tumor-derived CD4(+)CD25 (+) regulatory T cell suppression of dendritic cell function involves TGF-beta and IL-10. Cancer Immunol Immunother 2006; (in press).
79. Strobl H, Knapp W. TGF-beta1 regulation of dendritic cells. Microbes Infect 1999;1:1283-1290.
80. Weber F, et al. Transforming growth factor-beta1 immobilises dendritic cells within skin tumours and facilitates tumour escape from the immune system. Cancer Immunol Immunother 2005;54:898-906.
81. Huang RR, et al. Selective modulation of paracortical dendritic cells and T-lymphocytes in breast cancer sentinel lymph nodes. Breast J 2000;6:225-232.
82. Huang A, Gilmour JW, Imami N, Amjadi P, Henderson DC, Allen-Mersh TG. Increased serum transforming growth factor-beta1 in human colorectal cancer correlates with reduced circulating dendritic cells and increased colonic Langerhans cell infiltration. Clin Exp Immunol 2003;134:270-278.
83. Ito M, et al. Tumor-derived TGFbeta-1 induces dendritic cell apoptosis in the sentinel lymph node. J Immunol 2006;176:5637-5643.
84. Zhang X, et al. CD4-8- dendritic cells prime CD4+ T regulatory 1 cells to suppress antitumor immunity. J Immunol 2005;175:2931-2937.
85. Roncarolo MG, Levings MK, Traversari C. Differentiation of T regulatory cells by immature dendritic cells. J Exp Med 2001;193:F5-9.
86. Kapsenberg ML. Dendritic-cell control of pathogen-driven T-cell polarization. Nat Rev Immunol 2003;3:984-993.
87. Houot R, Perrot I, Garcia E, Durand I, Lebecque S. Human CD4+CD25 high regulatory T cells modulate myeloid but not plasmacytoid dendritic cells activation. J Immunol 2006;176:5293-5298.
88. Mellor AL, et al. Specific subsets of murine dendritic cells acquire potent T cell regulatory functions following CTLA4-mediated induction of indoleamine 2,3 dioxygenase. Int Immunol 2004;16:1391-1401.
89. Kao JY, Gong Y, Chen CM, Zheng QD, Chen JJ. Tumor-derived TGF-beta reduces the efficacy of dendritic cell/tumor fusion vaccine. J Immunol 2003;170:3806-3811.
90. Kobie JJ, et al. Transforming growth factor beta inhibits the antigen-presenting functions and antitumor activity of dendritic cell vaccines. Cancer Res 2003;63:1860-1864.
91. Wang RF, Peng G, Wang HY. Regulatory T cells and Toll-like receptors in tumor immunity. Semin Immunol 2006;18:136-142.
92. Chen W, Jin W, Cook M, Weiner HL, Wahl SM. Oral delivery of group A streptococcal cell walls augments circulating TGF-beta and suppresses streptococcal cell wall arthritis. J Immunol 1998;161:6297-6304.
93. Battaglia M, Gregori S, Bacchetta R, Roncarolo MG. Tr1 cells: from discovery to their clinical application. Semin Immunol 2006;18:120-127.
94. Kronenberg M. Toward an understanding of NKT cell biology: progress and paradoxes. Annu Rev Immunol 2005;23:877-900.
95. Terabe M, et al. CD1d-restricted natural killer T cells can down-regulate tumor immunosurveillance independent of interleukin-4 receptor-signal transducer and activator of transcription 6 or transforming growth factor-beta. Cancer Res 2006;66:3869-3875.
96. Waldmann H, et al. Regulatory T cells in transplantation. Semin Immunol 2006;18:111-119.
97. Sakaguchi S. Regulatory T cells: key controllers of immunologic self-tolerance. Cell 2000;101:455-458.
98. Shevach EM. CD4+ CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol 2002;2:389-400.
99. Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol 2005;6:1142-1151.
100. Bettelli E, Dastrange M, Oukka M. Foxp3 interacts with nuclear factor of activated T cells and NF-kappa B to repress cytokine gene expression and effector functions of T helper cells. Proc Natl Acad Sci USA 2005;102:5138-5143.
101. D'Cruz LM, Klein L. Development and function of agonist-induced CD25+Foxp3+ regulatory T cells in the absence of interleukin 2 signaling. Nat Immunol 2005;6:1152-1159.
102. Thornton AM, Donovan EE, Piccirillo CA, Shevach EM. Cutting edge: IL-2 is critically required for the in vitro activation of CD4+CD25+ T cell suppressor function. J Immunol 2004;172:6519-6523.
103. Wood KJ, Sakaguchi S. Regulatory T cells in transplantation tolerance. Nat Rev Immunol 2003;3:199-210.
104. Kingsley CI, Karim M, Bushell AR, Wood KJ. CD25+CD4+ regulatory T cells prevent graft rejection: CTLA-4- and IL-10-dependent immunoregulation of alloresponses. J Immunol 2002;168:1080-1086.
105. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995;155:1151-1164.
106. Zenclussen AC, et al. Regulatory T cells induce a privileged tolerant microenvironment at the fetal-maternal interface. Eur J Immunol 2006;36:82-94.
107. Sasaki Y, Sakai M, Miyazaki S, Higuma S, Shiozaki A, Saito S. Decidual and peripheral blood CD4+CD25+ regulatory T cells in early pregnancy subjects and spontaneous abortion cases. Mol Hum Reprod 2004;10:347-353.
108. Aluvihare VR, Kallikourdis M, Betz AG. Regulatory T cells mediate maternal tolerance to the fetus. Nat Immunol 2004;5:266-271.
109. Sakaguchi S. Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 2004;22:531-562.
110. Belkaid Y, Piccirillo CA, Mendez S, Shevach EM, Sacks DL. CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature 2002;420:502-507.
111. van Maurik A, Herber M, Wood KJ, Jones ND. Cutting edge: CD4+CD25+ alloantigen-specific immunoregulatory cells that can prevent CD8+ T cell-mediated graft rejection: implications for anti-CD154 immunotherapy. J Immunol 2002;169:5401-5404.
112. Sasada T, Kimura M, Yoshida Y, Kanai M, Takabayashi A. CD4+CD25+ regulatory T cells in patients with gastrointestinal malignancies: possible involvement of regulatory T cells in disease progression. Cancer 2003;98:1089-1099.
113. Khazaie K, von Boehmer H. The impact of CD4+CD25+ Treg on tumor specific CD8+ T cell cytotoxicity and cancer. Semin Cancer Biol 2006;16:124-136.
114. Ghiringhelli F, et al. CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-beta-dependent manner. J Exp Med 2005;202:1075-1085.
115. Wahl SM, Wen J, Moutsopoulos NM. The kiss of death: interrupted by NK-cell close encounters of another kind. Trends Immunol 2006;27:161-164.
116. Onizuka S, Tawara I, Shimizu J, Sakaguchi S, Fujita T, Nakayama E. Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Cancer Res 1999;59:3128-3133.
117. Sutmuller RP, et al. Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25(+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses. J Exp Med 2001;194:823-832.
118. Turk MJ, Guevara-Patino JA, Rizzuto GA, Engelhorn ME, Sakaguchi S, Houghton AN. Concomitant tumor immunity to a poorly immunogenic melanoma is prevented by regulatory T cells. J Exp Med 2004;200:771-782.
119. Woo EY, et al. Cutting edge: regulatory T cells from lung cancer patients directly inhibit autologous T cell proliferation. J Immunol 2002;168:4272-4276.
120. Curiel TJ, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 2004;10:942-949.
121. 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 beta. J Exp Med 2001;194:629-644.
122. Ostroukhova M, et al. Tolerance induced by inhaled antigen involves CD4(+) T cells expressing membrane-bound TGF-beta and FOXP3. J Clin Invest 2004;114:28-38.
123. Oida T, et al. CD4+CD25- T cells that express latency-associated peptide on the surface suppress CD4+CD45RB high-induced colitis by a TGF-beta-dependent mechanism. J Immunol 2003;170:2516-2522.
124. Green EA, Gorelik L, McGregor CM, Tran EH, Flavell RA. CD4+CD25+ T regulatory cells control anti-islet CD8+ T cells through TGF-beta-TGF-beta receptor interactions in type 1 diabetes. Proc Natl Acad Sci U S A 2003;100:10878-10883.
125. Powrie F, Carlino J, Leach MW, Mauze S, Coffman RL. A critical role for transforming growth factor-beta but not interleukin 4 in the suppression of T helper type 1-mediated colitis by CD45RB(low) CD4+ T cells. J Exp Med 1996;183:2669-2674.
126. Thornton AM, Shevach EM. Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific. J Immunol 2000;164:183-190.
127. Nakamura K, et al. TGF-beta 1 plays an important role in the mechanism of CD4+CD25+ regulatory T cell activity in both humans and mice. J Immunol 2004;172:834-842.
128. Fahlen L, et al. T cells that cannot respond to TGF-beta escape control by CD4(+)CD25(+) regulatory T cells. J Exp Med 2005;201:737-746.
129. Piccirillo CA, et al. CD4(+)CD25(+) regulatory T cells can mediate suppressor function in the absence of transforming growth factor beta1 production and responsiveness. J Exp Med 2002;196:237-246.
130. Marie JC, Letterio JJ, Gavin M, Rudensky AY. TGF-beta1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells. J Exp Med 2005;201:1061-1067.
131. Schubert LA, Jeffery E, Zhang Y, Ramsdell F, Ziegler SF. Scurfin (FOXP3) acts as a repressor of transcription and regulates T cell activation. J Biol Chem 2001;276:37672-37679.
132. Brunkow ME, et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet 2001;27:68-73.
133. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003;4:330-336.
134. 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.
135. Wildin RS, et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet 2001;27:18-20.
136. Bennett CL, et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 2001;27:20-21.
137. Boden E, Tang Q, Bour-Jordan H, Bluestone JA. The role of CD28 and CTLA4 in the function and homeostasis of CD4+CD25+ regulatory T cells. Novartis Found Symp 2003;252:55-63; discussion 6:106-114.
138. Chen W, Jin W, Wahl SM. Engagement of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) induces transforming growth factor beta (TGF-beta) production by murine CD4(+) T cells. J Exp Med 1998;188:1849-1857.
139. Gomes NA, Gattass CR, Barreto-De-Souza V, Wilson ME, DosReis GA. TGF-beta mediates CTLA-4 suppression of cellular immunity in murine kalaazar. J Immunol 2000;164:2001-2008.
140. Kitani A, Chua K, Nakamura K, Strober W. Activated self-MHC-reactive T cells have the cytokine phenotype of Th3/T regulatory cell 1 T cells. J Immunol 2000;165:691-702.
141. Esplugues E, et al. Enhanced antitumor immunity in mice deficient in CD69. J Exp Med 2003;197:1093-1106.
142. Zou W. Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer 2005;5:263-274.
143. Wei S, Kryczek I, Zou W. Regulatory T cell compartmentalization and trafficking. Blood 2006;108:426-431.
144. Taams LS, Akbar AN. Peripheral generation and function of CD4+CD25+ regulatory T cells. Curr Top Microbiol Immunol 2005;293:115-131.
145. Fantini MC, Becker C, Monteleone G, Pallone F, Galle PR, Neurath MF. Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25- T cells through Foxp3 induction and down-regulation of Smad7. J Immunol 2004;172:5149-5153.
146. Zheng SG, Wang JH, Gray JD, Soucier H, Horwitz DA. Natural and induced CD4+CD25+ cells educate CD4+CD25-cells to develop suppressive activity: the role of IL-2, TGF-beta, and IL-10. J Immunol 2004;172:5213-5221.
147. Wan YY, Flavell RA. Identifying Foxp3-expressing suppressor T cells with a bicistronic reporter. Proc Natl Acad Sci USA 2005;102:5126-5131.
148. Peng Y, Laouar Y, Li MO, Green EA, Flavell RA. TGF-beta regulates in vivo expansion of Foxp3-expressing CD4+CD25+ regulatory T cells responsible for protection against diabetes. Proc Natl Acad Sci USA 2004;101:4572-4577.
149. Huber S, et al. Cutting edge: TGF-beta signaling is required for the in vivo expansion and immunosuppressive capacity of regulatory CD4+CD25+ T cells. J Immunol 2004;173:6526-6531.
150. Chen W, et al. Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 2003;198:1875-1886.
151. Fantini MC, et al. Transforming growth factor {beta} induced FoxP3+ regulatory T cells suppress Th1 mediated experimental colitis. Gut 2006;55:671-680.
152. Park HB, Paik DJ, Jang E, Hong S, Youn J. Acquisition of anergic and suppressive activities in transforming growth factor-beta-costimulated CD4+CD25- T cells. Int Immunol 2004;16:1203-1213.
153. Cobbold SP, et al. Induction of foxP3+ regulatory T cells in the periphery of T cell receptor transgenic mice tolerized to transplants. J Immunol 2004;172:6003-6010.
154. Huber S, Schramm C. TGF-beta and CD4+CD25+ regulatory T cells. Front Biosci 2006;11:1014-1023.
155. Erdman SE, et al. CD4+CD25+ regulatory lymphocytes induce regression of intestinal tumors in ApcMin/+ mice. Cancer Res 2005;65:3998-4004.
156. Coffman RL, Mocci S, O'Garra A. The stability and reversibility of Th1 and Th2 populations. Curr Top Microbiol Immunol 1999;238:1-12.
157. Becker Y. Molecular immunological approaches to biotherapy of human cancers - a review, hypothesis and implications. Anticancer Res 2006;26:1113-1134.
158. Vonderheide RH, June CH. A translational bridge to cancer immunotherapy: exploiting costimulation and target antigens for active and passive T cell immunotherapy. Immunol Res 2003;27:341-356.
159. Chen ML, et al. Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-beta signals in vivo. Proc Natl Acad Sci USA 2005;102:419-424.
160. Nagy N, Vanky F. Transforming growth factor beta, (TGFbeta) secreted by immunogenic ex vivo human carcinoma cells, counteracts the activation and inhibits the function of autologous cytotoxic lymphocytes. Pretreatment with interferon gamma and tumor necrosis factor alpha reduces the production of active TGFbeta. Cancer Immunol Immunother 1998;45:306-312.
161. Gorelik L, Flavell RA. Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells. Nat Med 2001;7:1118-1122.
162. Ahmadzadeh M, Rosenberg SA. TGF-beta 1 attenuates the acquisition and expression of effector function by tumor antigen-specific human memory CD8 T cells. J Immunol 2005;174:5215-5223.
163. Thomas DA, Massague J. TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell 2005;8:369-380.
164. Hayakawa Y, et al. IFN-gamma-mediated inhibition of tumor angiogenesis by natural killer T-cell ligand, alpha-galactosylceramide. Blood 2002;100:1728-1733.
165. Smyth MJ, Crowe NY, Godfrey DI. NK cells and NKT cells collaborate in host protection from methylcholanthrene-induced fibrosarcoma. Int Immunol 2001;13:459-463.
166. Rook AH, et al. Effects of transforming growth factor beta on the functions of natural killer cells: depressed cytolytic activity and blunting of interferon responsiveness. J Immunol 1986;136:3916-3920.
167. Smyth MJ, Teng MW, Swann J, Kyparissoudis K, Godfrey DI, Hayakawa Y. CD4+CD25+ T regulatory cells suppress NK cell-mediated immunotherapy of cancer. J Immunol 2006;176:1582-1587.
168. Moffett-King A. Natural killer cells and pregnancy. Nat Rev Immunol 2002;2:656-663.
169. Bowen JM, Chamley L, Mitchell MD, Keelan JA. Cytokines of the placenta and extra-placental membranes: biosynthesis, secretion and roles in establishment of pregnancy in women. Placenta 2002;23:239-256.
170. Heikkinen J, Mottonen M, Alanen A, Lassila O. Phenotypic characterization of regulatory T cells in the human decidua. Clin Exp Immunol 2004;136:373-378.
171. Aluvihare VR, Kallikourdis M, Betz AG. Tolerance, suppression and the fetal allograft. J Mol Med 2005;83:88-96.
172. Somerset DA, Zheng Y, Kilby MD, Sansom DM, Drayson MT. Normal human pregnancy is associated with an elevation in the immune suppressive CD25+ CD4+ regulatory T-cell subset. Immunology 2004;112:38-43.
173. Finberg RW, et al. Selective elimination of HIV-1-infected cells with an interleukin-2 receptor-specific cytotoxin. Science 1991;252:1703-1705.
174. Steitz J, Bruck J, Lenz J, Knop J, Tuting T. Depletion of CD25(+) CD4(+) T cells and treatment with tyrosinase-related protein 2-transduced dendritic cells enhance the interferon alpha-induced, CD8(+) T-cell-dependent immune defense of B16 melanoma. Cancer Res 2001;61:8643-8646.
175. Moseley TA, Haudenschild DR, Rose L, Reddi AH. Interleukin-17 family and IL-17 receptors. Cytokine Growth Factor Rev 2003;14:155-174.
176. Kolls JK, Linden A. Interleukin-17 family members and inflammation. Immunity 2004;21:467-476.
177. Numasaki M, et al. Interleukin-17 promotes angiogenesis and tumor growth. Blood 2003;101:2620-2627.
178. Numasaki M, et al. IL-17 enhances the net angiogenic activity and in vivo growth of human non-small cell lung cancer in SCID mice through promoting CXCR-2-dependent angiogenesis. J Immunol 2005;175:6177-6189.
179. Tartour E, et al. Interleukin 17, a T-cell-derived cytokine, promotes tumorigenicity of human cervical tumors in nude mice. Cancer Res 1999;59:3698-3704.
180. Ciree A, et al. Expression and activity of IL-17 in cutaneous T-cell lymphomas (mycosis fungoides and Sezary syndrome). Int J Cancer 2004;112:113-120.
181. Kato T, et al. Expression of IL-17 mRNA in ovarian cancer. Biochem Biophys Res Commun 2001;282:735-738.
182. Folkman J, Watson K, Ingber D, Hanahan D. Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature 1989;339:58-61.
183. Ferretti S, Bonneau O, Dubois GR, Jones CE, Trifilieff A. IL-17, produced by lymphocytes and neutrophils, is necessary for lipopolysaccharide-induced airway neutrophilia: IL-15 as a possible trigger. J Immunol 2003;170:2106-2112.
184. Aggarwal S, Ghilardi N, Xie MH, de Sauvage FJ, Gurney AL. Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem 2003;278:1910-1914.
185. Dong C. Diversification of T-helper-cell lineages: finding the family root of IL-17-producing cells. Nat Rev Immunol 2006;6:329-334.
186. Park H, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 2005;6:1133-1141.
187. Harrington LE, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 2005;6:1123-1132.
188. Happel KI, et al. Cutting edge: roles of Toll-like receptor 4 and IL-23 in IL-17 expression in response to Klebsiella pneumoniae infection. J Immunol 2003;170:4432-4436.
189. Bettelli E, et al. Reciprocal developmental pathways for the generation of pathogenic effector (TH-IL-17) and regulatory (CD4+CD25+Foxp3+) T cells. Nature 2006;441:235-238.
190. Whiteside TL. The role of immune cells in the tumor microenvironment. Cancer Treat Res 2006;130:103-124.
191. Roberts AB, Sporn MB. Regulation of endothelial cell growth, architecture, and matrix synthesis by TGF-beta. Am Rev Respir Dis 1989;140:1126-1128.
192. Rouvier E, Luciani MF, Mattei MG, Denizot F, Golstein P. CTLA-8, cloned from an activated T cell, bearing AU-rich messenger RNA instability sequences, and homologous to a herpesvirus saimiri gene. J Immunol 1993;150:5445-5456.
193. Yao Z, et al. Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor. Immunity 1995;3:811-821.
194. Hurst SD, et al. New IL-17 family members promote Th1 or Th2 responses in the lung: in vivo function of the novel cytokine IL-25. J Immunol 2002;169:443-453.
195. Fort MM, et al. IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity 2001;15:985-995.
196. Starnes T, et al. Cutting edge: IL-17F, a novel cytokine selectively expressed in activated T cells and monocytes, regulates angiogenesis and endothelial cell cytokine production. J Immunol 2001;167:4137-4140.
197. Gattinoni L, Powell DJ, Rosenberg SA, Restifo NP. Adoptive immunotherapy for cancer: building on success. Nat Rev Immunol 2006;6:383-393.
198. Huehn J, Siegmund K, Hamann A. Migration rules: functional properties of naive and effector/memory-like regulatory T cell subsets. Curr Top Microbiol Immunol 2005;293:89-114.
199. Schlingensiepen KH, et al. Targeted tumor therapy with the TGF-beta2 antisense compound AP 12009. Cytokine Growth Factor Rev 2006;17:129-139.