Current status of interleukin-10 and regulatory T-cells in cancer

Current Opinion in Oncology

Volumn 25, Issue 6, 2013, Pages 637-645

  Dennis, Kristen L ^a   Blatner, Nichole R ^a   Gounari, Fotini ^b   Khazaie, Khashayarsha ^a  

^a NORTHWESTERN UNIVERSITY   (United States)

^b UNIVERSITY OF CHICAGO   (United States)

Author keywords

cancer; immune surveillance; inflammation; interleukin 10; tregs

Indexed keywords

CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; INTERLEUKIN 10; INTERLEUKIN 12; INTERLEUKIN 17; INTERLEUKIN 2 RECEPTOR ALPHA; INTERLEUKIN 27; INTERLEUKIN 6; MAJOR HISTOCOMPATIBILITY ANTIGEN CLASS 2; PROTEIN TYROSINE PHOSPHATASE SHP 1; STAT3 PROTEIN; TRANSCRIPTION FACTOR FOXP3; TUMOR NECROSIS FACTOR ALPHA;

ADENOMATOUS POLYP; ANTIGEN PRESENTATION; ANTIGEN PRESENTING CELL; B LYMPHOCYTE; BREAST CANCER; CD8+ T LYMPHOCYTE; COLON CANCER; CYTOKINE PRODUCTION; CYTOTOXICITY; DENDRITIC CELL; DOWN REGULATION; HELPER CELL; HUMAN; IMMUNE RESPONSE; IMMUNOSTIMULATION; IMMUNOSUPPRESSIVE TREATMENT; IMMUNOSURVEILLANCE; INFLAMMATION; INSULIN DEPENDENT DIABETES MELLITUS; LEISHMANIA MAJOR; LUNG CANCER; LYMPHOCYTE FUNCTION; LYMPHOCYTE PROLIFERATION; MAST CELL; NONHUMAN; PANCREAS CANCER; PHENOTYPE; PLEIOTROPY; PRIORITY JOURNAL; PROSTATE CANCER; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; REGULATORY T LYMPHOCYTE; REVIEW; SIGNAL TRANSDUCTION; T LYMPHOCYTE ACTIVATION; TH17 CELL; TH2 CELL;

ANIMALS; ANTIGENS, NEOPLASM; CELL LINE, TUMOR; CELL PROLIFERATION; DENDRITIC CELLS; FEMALE; HUMANS; IMMUNE TOLERANCE; IMMUNOMODULATION; INTERLEUKIN-10; LYMPHOCYTE ACTIVATION; MALE; MICE; NEOPLASMS; T-LYMPHOCYTE SUBSETS; T-LYMPHOCYTES, REGULATORY;

EID: 84885433913     PISSN: 10408746     EISSN: 1531703X     Source Type: Journal    
DOI: 10.1097/CCO.0000000000000006     Document Type: Review

References (186)

1. De Plaen E, Lurquin C, Van Pel A, et al. Immunogenic (tum-) variantsof mouse tumor P815: cloning of the gene of tum-antigen P91A and identification of the tum-mutation. Proc Natl Acad Sci U S A 1988; 85:2274-2278.
2. Degiovanni G, Lahaye T, Herin M, et al. Antigenic heterogeneity of a human melanoma tumor detected by autologous CTL clones. Eur J Immunol 1988; 18:671-676.
3. Van den Eynde B, Lethe B, Van Pel A, et al. The gene coding for a major tumor rejection antigen of tumor P815 is identical to the normal gene of syngeneic DBA/2 mice. J Exp Med 1991; 173:1373-1384.
4. Knuth A, Wolfel T, Klehmann E, et al. Cytolytic T-cell clones against an autologous human melanoma: specificity study and definition of three antigens by immunoselection. Proc Natl Acad Sci U S A 1989; 86:2804-2808.
5. Bruno L, Kirberg J, von Boehmer H. On the cellular basis of immunological T cell memory. Immunity 1995; 2:37-43.
6. Sakaguchi S, Sakaguchi N, Asano M, et al. 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.
7. Moore KW, O'Garra A, de Waal Malefyt R, et al. Interleukin-10. Annu Rev Immunol 1993; 11:165-190.
8. Grakoui A, Shoukry NH, Woollard DJ, et al. HCV persistence and immune evasion in the absence of memory T cell help. Science 2003; 302:659-662.
9. Janssen EM, Lemmens EE, Wolfe T, et al. CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature 2003; 421:852-856.
10. Shedlock DJ, Shen H. Requirement for CD4 T cell help in generating functional CD8 T cell memory. Science 2003; 300:337-339.
11. Sun JC, Bevan MJ. Defective CD8 T cell memory following acute infection without CD4 T cell help. Science 2003; 300:339-342.
12. Gately MK, Gubler U, Brunda MJ, et al. Interleukin-12: a cytokine with therapeutic potential in oncology and infectious diseases. Ther Immunol 1994; 1:187-196.
13. van Den Broek M, Bachmann MF, Kohler G, et al. IL-4 and IL-10 antagonize IL-12-mediated protection against acute vaccinia virus infection with a limited role of IFN-gamma and nitric oxide synthetase 2. J Immunol 2000; 164:371-378.
14. Shurin MR, Lu L, Kalinski P, et al. Th1/Th2 balance in cancer, transplantation and pregnancy. Springer Semin Immunopathol 1999; 21:339-359.
15. Khazaie K, Bonertz A, Beckhove P. Current developments with peptide-based human tumor vaccines. Curr Opin Oncol 2009; 21:524-530.
16. 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.
17. Mumm JB, Oft M. Pegylated IL-10 induces cancer immunity: the surprising role of IL-10 as a potent inducer of IFN-gamma-mediated CD8(+) T cell cytotoxicity. Bioessays 2013; 35:623-631.
18. Maloy KJ, Salaun L, Cahill R, et al. CD4+CD25+ T(R) cells suppress innate immune pathology through cytokine-dependent mechanisms. J Exp Med 2003; 197:111-119.
19. Maynard CL, Harrington LE, Janowski KM, et al. Regulatory T cells expressing interleukin 10 develop from Foxp3+ and Foxp3-precursor cells in the absence of interleukin 10. Nat Immunol 2007; 8:931-941.
20. Maloy KJ, Powrie F. Regulatory T cells in the control of immune pathology. Nat Immunol 2001; 2:816-822.
21. McGuirk P, McCann C, Mills KH. Pathogen-specific T regulatory 1 cells induced in the respiratory tract by a bacterial molecule that stimulates interleukin 10 production by dendritic cells: a novel strategy for evasion of protective T helper type 1 responses by Bordetella pertussis. J Exp Med 2002; 195:221-231.
22. O'Garra A, Vieira PL, Vieira P, Goldfeld AE. IL-10-producing and naturally occurring CD4+ Tregs: limiting collateral damage. J Clin Invest 2004; 114:1372-1378.
23. Roncarolo MG, Gregori S, Battaglia M, et al. Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol Rev 2006; 212:28-50.
24. O'Garra A, Stapleton G, Dhar V, et al. Production of cytokines by mouse B cells: B lymphomas and normal B cells produce interleukin 10. Int Immunol 1990; 2:821-832.
25. Burdin N, Rousset F, Banchereau J. B-cell-derived IL-10: production and function. Methods 1997; 11:98-111.
26. Fillatreau S, Sweenie CH, McGeachy MJ, et al. B cells regulate autoimmunity by provision of IL-10. Nat Immunol 2002; 3:944-950.
27. Mauri C, Gray D, Mushtaq N, Londei M. Prevention of arthritis by interleukin 10-producing B cells. J Exp Med 2003; 197:489-501.
28. O'Garra A, Chang R, Go N, et al. Ly-1 B (B-1) cells are the main source of B cell-derived interleukin 10. Eur J Immunol 1992; 22:711-717.
29. Boonstra A, Rajsbaum R, Holman M, et al. Macrophages and myeloid dendritic cells, but not plasmacytoid dendritic cells, produce IL-10 in response to MyD88-and TRIF-dependent TLR signals, and TLR-independent signals. J Immunol 2006; 177:7551-7558.
30. Dillon S, Agrawal A, Van Dyke T, et al. A toll-like receptor 2 ligand stimulates Th2 responses in vivo, via induction of extracellular signal-regulated kinase mitogen-activated protein kinase and c-Fos in dendritic cells. J Immunol 2004; 172:4733-4743.
31. Edwards AD, Manickasingham SP, Sporri R, et al. Microbial recognition via toll-like receptor-dependent and-independent pathways determines the cytokine response of murine dendritic cell subsets to CD40 triggering. J Immunol 2002; 169:3652-3660.
32. Tanchot C, Guillaume S, Delon J, et al. Modifications of CD8+ T cell function during in vivo memory or tolerance induction. Immunity 1998; 8:581-590.
33. Anderson CF, Oukka M, Kuchroo VJ, Sacks D. CD4(+)CD25(-)Foxp3(-) Th1 cells are the source of IL-10-mediated immune suppression in chronic cutaneous leishmaniasis. J Exp Med 2007; 204:285-297.
34. Belkaid Y, Hoffmann KF, Mendez S, et al. The role of interleukin (IL)-10 in the persistence of Leishmania major in the skin after healing and the therapeutic potential of anti-IL-10 receptor antibody for sterile cure. J Exp Med 2001; 194:1497-1506.
35. Gerosa F, Nisii C, Righetti S, et al. CD4(+) T cell clones producing both interferon-gamma and interleukin-10 predominate in bronchoalveolar lavages of active pulmonary tuberculosis patients. Clin Immunol 1999; 92:224-234.
36. Jankovic D, Kullberg MC, Feng CG, et al. Conventional T-bet(+)Foxp3(-) Th1 cells are the major source of host-protective regulatory IL-10 during intra-cellular protozoan infection. J Exp Med 2007; 204:273-283.
37. Jankovic D, Kullberg MC, Hieny S, et al. In the absence of IL-12, CD4(+) T cell responses to intracellular pathogens fail to default to a Th2 pattern and are host protective in an IL-10(-/-) setting. Immunity 2002; 16:429-439.
38. Jeannin P, Delneste Y, Seveso M, et al. IL-12 synergizes with IL-2 and other stimuli in inducing IL-10 production by human T cells. J Immunol 1996; 156:3159-3165.
39. Meyaard L, Hovenkamp E, Otto SA, Miedema F. IL-12-induced IL-10 production by human T cells as a negative feedback for IL-12-induced immune responses. J Immunol 1996; 156:2776-2782.
40. Pohl-Koppe A, Balashov KE, Steere AC, et al. Identification of a T cell subset capable of both IFN-gamma and IL-10 secretion in patients with chronic Borrelia burgdorferi infection. J Immunol 1998; 160:1804-1810.
41. Shaw MH, Freeman GJ, Scott MF, et al. Tyk2 negatively regulates adaptive Th1 immunity by mediating IL-10 signaling and promoting IFN-gamma-dependent IL-10 reactivation. J Immunol 2006; 176:7263-7271.
42. Windhagen A, Anderson DE, Carrizosa A, et al. IL-12 induces human T cells secreting IL-10 with IFN-gamma. J Immunol 1996; 157:1127-1131.
43. O'Garra A, Vieira P. T(H)1 cells control themselves by producing interleukin-10. Nat Rev Immunol 2007; 7:425-428.
44. Trinchieri G. Interleukin-10 production by effector T cells: Th1 cells show self control. J Exp Med 2007; 204:239-243.
45. Maynard CL, Weaver CT. Intestinal effector T cells in health and disease. Immunity 2009; 31:389-400.
46. Murai M, Turovskaya O, Kim G, et al. Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis. Nat Immunol 2009; 10:1178-1184.
47. Dennis KL, Wang YW, Blatner NB, et al. Adenomatous polyps are driven by microbe-instigated focal inflammation and are controlled by IL-10 producing T-cells. Cancer Res 2013; in press.
48. Annacker O, Asseman C, Read S, Powrie F. Interleukin-10 in the regulation of T cell-induced colitis. J Autoimmun 2003; 20:277-279.
49. Fiorentino DF, Bond MW, Mosmann TR. Two typesof mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med 1989; 170:2081-2095.
50. Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 2001; 19:683-765.
51. Trinchieri G. Regulatory role of T cells producing both interferon gamma and interleukin 10 in persistent infection. J Exp Med 2001; 194:F53-57.
52. Sacks D, Anderson C. Re-examination of the immunosuppressive mechanisms mediating non-cure of Leishmania infection in mice. Immunol Rev 2004; 201:225-238.
53. De Santo C, Arscott R, Booth S, et al. Invariant NKT cells modulate the suppressive activity of IL-10-secreting neutrophils differentiated with serum amyloid A. Nat Immunol 2010; 11:1039-1046.
54. Kim J, Modlin RL, Moy RL, et al. IL-10 production in cutaneous basal and squamous cell carcinomas. A mechanism for evading the local T cell immune response. J Immunol 1995; 155:2240-2247.
55. Steinbrink K, Jonuleit H, Muller G, et al. Interleukin-10-treated human dendritic cells induce a melanoma-antigen-specific anergy in CD8(+) T cells resulting in a failure to lyse tumor cells. Blood 1999; 93:1634-1642.
56. Urosevic M, Dummer R. HLA-GandIL-10expressioninhumancancer:different stories with the same message. Semin Cancer Biol 2003; 13:337-342.
57. Kim BG, Joo HG, Chung IS, et al. Inhibition of interleukin-10 (IL-10) production from MOPC 315 tumor cells by IL-10 antisense oligodeoxynu-cleotides enhances cell-mediated immune responses. Cancer Immunol Immunother 2000; 49:433-440.
58. Matar P, Rozados VR, Gervasoni SI, Scharovsky OG. Down regulation of T-cell-derived IL-10 production by low-dose cyclophosphamide treatment in tumor-bearing rats restores in vitro normal lymphoproliferative response. Int Immunopharmacol 2001; 1:307-319.
59. Vicari AP, Chiodoni C, Vaure C, et al. Reversal of tumor-induced dendritic cell paralysis by CpG immunostimulatory oligonucleotide and anti-interleukin 10 receptor antibody. J Exp Med 2002; 196:541-549.
60. Stolina M, Sharma S, Lin Y, et al. Specific inhibition of cyclooxygenase 2 restores antitumor reactivity by altering the balance of IL-10 and IL-12 synthesis. J Immunol 2000; 164:361-370.
61. Caux C, Massacrier C, Vanbervliet B, et al. Interleukin 10 inhibits T cell alloreaction induced by human dendritic cells. Int Immunol 1994; 6:1177-1185.
62. de Waal Malefyt R, Yssel H, de Vries JE. Direct effects of IL-10 on subsets of human CD4+ T cell clones and resting T cells. Specific inhibition of IL-2 production and proliferation. J Immunol 1993; 150:4754-4765.
63. Del Prete G, De Carli M, Almerigogna F, et al. Human IL-10 is produced by both type 1 helper (Th1) and type 2 helper (Th2) T cell clones and inhibits their antigen-specific proliferation and cytokine production. J Immunol 1993; 150:353-360.
64. Groux H, Bigler M, de Vries JE, Roncarolo MG. Interleukin-10 induces a longterm antigen-specific anergic state in human CD4+ T cells. J Exp Med 1996; 184:19-29.
65. Jinquan T, Quan S, Jacobi HH, et al. CXC chemokine receptor 4 expression and stromal cell-derived factor-1alpha-induced chemotaxis in CD4+ T lymphocytes are regulated by interleukin-4 and interleukin-10. Immunology 2000; 99:402-410.
66. Taga K, Mostowski H, Tosato G. Human interleukin-10 can directly inhibit T-cell growth. Blood 1993; 81:2964-2971.
67. Mocellin S, Marincola F, Rossi CR, et al. The multifaceted relationship between IL-10 and adaptive immunity: putting together the pieces of a puzzle. Cytokine Growth Factor Rev 2004; 15:61-76.
68. Buer J, Lanoue A, Franzke A, et al. Interleukin 10 secretion and impaired effector function of major histocompatibility complex class II-restricted T cells anergized in vivo. J Exp Med 1998; 187:177-183.
69. Asadullah K, Sterry W, Volk HD. Interleukin-10 therapy: review of a new approach. Pharmacol Rev 2003; 55:241-269.
70. Mocellin S, Marincola FM, Young HA. Interleukin-10 and the immune response against cancer: a counterpoint. JLeukoc Biol 2005; 78:1043-1051.
71. Steinbrink K, Graulich E, Kubsch S, et al. CD4(+) and CD8(+) anergic T cells induced by interleukin-10-treated human dendritic cells display antigen-specific suppressor activity. Blood 2002; 99:2468-2476.
72. Akbari O, DeKruyff RH, Umetsu DT. Pulmonary dendritic cells producing IL-10 mediate tolerance induced by respiratory exposure to antigen. Nat Immunol 2001; 2:725-731.
73. Wakkach A, Fournier N, Brun V, et al. Characterization of dendritic cells that induce tolerance and T regulatory 1 cell differentiation in vivo. Immunity 2003; 18:605-617.
74. Lang R, Patel D, Morris JJ, et al. Shaping gene expression in activated and resting primary macrophages by IL-10. J Immunol 2002; 169:2253-2263.
75. Scott-Browne JP, Shafiani S, Tucker-Heard G, et al. Expansion and function of Foxp3-expressing T regulatory cells during tuberculosis. J Exp Med 2007; 204:2159-2169.
76. Shafiani S, Tucker-Heard G, Kariyone A, et al. Pathogen-specific regulatory T cells delay the arrival of effector T cells in the lung during early tuberculosis. J Exp Med 2010; 207:1409-1420.
77. Sharma PK, Saha PK, Singh A, et al. FoxP3+ regulatory T cells suppress effector T-cell function at pathologic site in miliary tuberculosis. Am J Respir Crit Care Med 2009; 179:1061-1070.
78. Zhang H, Stern JN, Strominger JL. T cell receptors in an IL-10-secreting amino acid copolymer-specific regulatory T cell line that mediates bystander immunosuppression. Proc Natl Acad Sci U S A 2009; 106:3336-3341.
79. Murai M, Krause P, Cheroutre H, Kronenberg M. Regulatory T-cell stability and plasticity in mucosal and systemic immune systems. Mucosal Immunol 2010; 3:443-449.
80. Maldonado RA, von Andrian UH. How tolerogenic dendritic cells induce regulatory T cells. Adv Immunol 2010; 108:111-165.
81. Levings MK, Bacchetta R, Schulz U, Roncarolo MG. The role of IL-10 and TGF-beta in the differentiation and effector function of T regulatory cells. Int Arch Allergy Immunol 2002; 129:263-276.
82. Seder RA, Marth T, Sieve MC, et al. Factors involved in the differentiation of TGF-beta-producing cells from naive CD4+ T cells: IL-4 and IFN-gamma have opposing effects, while TGF-beta positively regulates its own production. J Immunol 1998; 160:5719-5728.
83. Tsuji-Takayama K, Suzuki M, Yamamoto M, et al. The production of IL-10 by human regulatory T cells is enhanced by IL-2 through a STAT5-responsive intronic enhancer in the IL-10 locus. J Immunology 2008; 181:3897-3905.
84. Awasthi A, Carrier Y, Peron JP, et al. A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells. Nat Immunol 2007; 8:1380-1389.
85. Fitzgerald DC, Zhang GX, El-Behi M, et al. Suppression of autoimmune inflammation of the central nervous system by interleukin 10 secreted by interleukin 27-stimulated T cells. Nat Immunol 2007; 8:1372-1379.
86. Stumhofer JS, Silver JS, Laurence A, et al. Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10. Nat Immunol 2007; 8:1363-1371.
87. Levings MK, Sangregorio R, Galbiati F, et al. IFN-alpha and IL-10 induce the differentiation of human type 1 T regulatory cells. J Immunol 2001; 166:5530-5539.
88. Roncarolo MG, Bacchetta R, Bordignon C, et al. Type 1 T regulatory cells. Immunol Rev 2001; 182:68-79.
89. Curiel TJ, Wei S, Dong H, et al. Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat Med 2003; 9:562-567.
90. Akdis CA, Blaser K. Mechanisms of interleukin-10-mediated immune suppression. Immunology 2001; 103:131-136.
91. Darrah PA, Hegde ST, Patel DT, et al. IL-10 production differentially influences the magnitude, quality, and protective capacity of Th1 responses depending on the vaccine platform. J Exp Med 2010; 207:1421-1433.
92. Lee MS, Mueller R, Wicker LS, et al. IL-10 is necessary and sufficient for autoimmune diabetes in conjunction with NOD MHC homozygosity. J Exp Med 1996; 183:2663-2668.
93. Pennline KJ, Roque-Gaffney E, Monahan M. Recombinant human IL-10 prevents the onset of diabetes in the nonobese diabetic mouse. Clin Immunol Immunopathol 1994; 71:169-175.
94. Kurte M, Lopez M, Aguirre A, et al. A synthetic peptide homologous to functional domain of human IL-10 down-regulates expression of MHC class I and transporter associated with antigen processing 1/2 in human melanoma cells. J Immunol 2004; 173:1731-1737.
95. Petersson M, Charo J, Salazar-Onfray F, et al. Constitutive IL-10 production accounts for the high NK sensitivity, low MHC class I expression, and poor transporter associated with antigen processing (TAP)-1/2 function in the prototype NK target YAC-1. J Immunol 1998; 161:2099-2105.
96. Maynard CL, Weaver CT. Diversity in the contribution of interleukin-10 to T-cell-mediated immune regulation. Immunol Rev 2008; 226:219-233.
97. Murray PJ. The primary mechanism of the IL-10-regulated antiinflammatory response is to selectively inhibit transcription. Proc Natl Acad Sci U S A 2005; 102:8686-8691.
98. Murray PJ. Understanding and exploiting the endogenous interleukin-10/STAT3-mediated anti-inflammatory response. Curr Opin Pharmacol 2006; 6:379-386.
99. Moore A, Josephson L, Bhorade RM, et al. Human transferrin receptor gene as a marker gene for MR imaging. Radiology 2001; 221:244-250.
100. Perrier P, Martinez FO, Locati M, et al. Distinct transcriptional programs activated by interleukin-10 with or without lipopolysaccharide in dendritic cells: induction of the B cell-activating chemokine, CXC chemokine ligand 13. J Immunol 2004; 172:7031-7042.
101. Akdis CA, Joss A, Akdis M, Blaser K. Mechanism of IL-10-induced T cell inactivation in allergic inflammation and normal response to allergens. Int Arch Allergy Immunol 2001; 124:180-182.
102. Veillette A, Latour S. The SLAM family of immune-cell receptors. Curr Opin Immunol 2003; 15:277-285.
103. Akdis CA, Blaser K. Mechanisms of allergen-specific immunotherapy. Allergy 2000; 55:522-530.
104. Akdis CA, Joss A, Akdis M, et al. A molecular basis for T cell suppression by IL-10: CD28-associated IL-10 receptor inhibits CD28 tyrosine phosphoryla-tion and phosphatidylinositol 3-kinase binding. FASEB J 2000; 14:1666-1668.
105. Joss A, Akdis M, Faith A, et al. IL-10 directly acts on T cells by specifically altering the CD28 co-stimulation pathway. Eur J Immunol 2000; 30:1683-1690.
106. Taylor A, Akdis M, Joss A, et al. IL-10 inhibits CD28 and ICOS costimulations of Tcells via src homology2domain-containing protein tyrosine phosphatase 1. J Allergy Clin Immunol 2007; 120:76-83.
107. Taylor A, Verhagen J, Akkoc T, et al. IL-10 suppresses CD2-mediated T cell activation via SHP-1. Mol Immunol 2009; 46:622-629.
108. Croker BA, Krebs DL, Zhang JG, et al. SOCS3 negatively regulates IL-6 signaling in vivo. Nat Immunol 2003; 4:540-545.
109. Fiorentino DF, Zlotnik A, Mosmann TR, et al. IL-10 inhibits cytokine production by activated macrophages. J Immunol 1991; 147:3815-3822.
110. Chen Z, Laurence A, Kanno Y, et al. Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells. Proc Natl Acad Sci U S A 2006; 103:8137-8142.
111. Pasare C, Medzhitov R. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 2003; 299:1033-1036.
112. Piconese S, Gri G, Tripodo C, et al. Mast cells counteract regulatory T-cell suppression through interleukin-6 and OX40/OX40L axis toward Th17-cell differentiation. Blood 2009; 114:2639-2648.
113. Blatner NR, Bonertz A, Beckhove P, et al. In colorectal cancer mast cells contribute to systemic regulatory T-cell dysfunction. Proc Natl Acad Sci U SA 2010; 107:6430-6435.
114. Go NF, Castle BE, Barrett R, et al. Interleukin 10, a novel B cell stimulatory factor: unresponsiveness of X chromosome-linked immunodeficiencyB cells. J Exp Med 1990; 172:1625-1631.
115. MacNeil IA, Suda T, Moore KW, et al. IL-10, a novel growth cofactor for mature and immature T cells. J Immunol 1990; 145:4167-4173.
116. Vieira P, de Waal-Malefyt R, Dang MN, et al. Isolation and expression of human cytokine synthesis inhibitory factor cDNA clones: homology to Epstein-Barr virus open reading frame BCRFI. Proc Natl Acad Sci U S A 1991; 88:1172-1176.
117. Chen WF, Zlotnik A. IL-10: a novel cytotoxic T cell differentiation factor. J Immunol 1991; 147:528-534.
118. Kang SS, Allen PM. Priming in the presence of IL-10 results in direct enhancement of CD8+ T cell primary responses and inhibition of secondary responses. J Immunol 2005; 174:5382-5389.
119. Cai G, Kastelein RA, Hunter CA. IL-10 enhances NK cell proliferation, cytotoxicity and production of IFN-gamma when combined with IL-18. Eur J Immunol 1999; 29:2658-2665.
120. Groux H, Cottrez F, Rouleau M, et al. A transgenic model to analyze the immunoregulatory role of IL-10 secreted by antigen-presenting cells. J Immunol 1999; 162:1723-1729.
121. Kundu N, Beaty TL, Jackson MJ, Fulton AM. Antimetastatic and antitumor activities of interleukin 10 in a murine model of breast cancer. J Natl Cancer Inst 1996; 88:536-541.
122. Zheng LM, Ojcius DM, Garaud F, et al. Interleukin-10 inhibits tumor metastasis through an NKcell-dependent mechanism. J Exp Med 1996; 184:579-584.
123. Giovarelli M, Musiani P, Modesti A, et al. Local release of IL-10 by transfected mouse mammary adenocarcinoma cells does not suppress but enhances antitumor reaction and elicits a strong cytotoxic lymphocyte and antibody-dependent immune memory. J Immunol 1995; 155:3112-3123.
124. Berman RM, Suzuki T, Tahara H, et al. Systemic administration of cellular IL-10 induces an effective, specific, and long-lived immune response against established tumors in mice. J Immunol 1996; 157:231-238.
125. Fujii S, Shimizu K, Shimizu T, Lotze MT. Interleukin-10 promotes the maintenance of antitumor CD8(+) T-cell effector function in situ. Blood 2001; 98:2143-2151.
126. Mumm JB, Emmerich J, Zhang X, et al. IL-10 elicits IFNgamma-dependent tumor immune surveillance. Cancer Cell 2011; 20:781-796.
127. + T-cells, and intratumoral antigen presentation molecules.
128. Ebert EC. IL-10 enhances IL-2-induced proliferation and cytotoxicity by human intestinal lymphocytes. Clin Exp Immunol 2000; 119:426-432.
129. Santin AD, Hermonat PL, Ravaggi A, et al. Interleukin-10 increases Th1 cytokine production and cytotoxic potential in human papillomavirus-specific CD8(+) cytotoxic T lymphocytes. J Virol 2000; 74:4729-4737.
130. Groux H, Bigler M, de Vries JE, Roncarolo MG. Inhibitory and stimulatory effects of IL-10 on human CD8+ T cells. J Immunol 1998; 160:3188-3193.
131. Dardalhon V, Awasthi A, Kwon H, et al. IL-4 inhibits TGF-beta-induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3(-) effector T cells. Nat Immunol 2008; 9:1347-1355.
132. Gajewski TF, Woo SR, Zha Y, et al. Cancer immunotherapy strategies based on overcoming barriers within the tumor microenvironment. Curr Opin Immunol 2013; 25:268-276.
133. Muranski P, Boni A, Antony PA, et al. Tumor-specific Th17-polarized cells eradicate large established melanoma. Blood 2008; 112:362-373.
134. Martin-Orozco N, Muranski P, Chung Y, et al. T helper 17 cells promote cytotoxic t cell activation in tumor immunity. Immunity 2009; 31:787-798.
135. Hinrichs CS, Kaiser A, Paulos CM, et al. Type 17 CD8+ T cells display enhanced antitumor immunity. Blood 2009; 114:596-599.
136. Ma Y, Conforti R, Aymeric L, et al. How to improve the immunogenicity of chemotherapy and radiotherapy. Cancer Metastasis Rev 2011; 30:71-82.
137. Ghiringhelli F, Apetoh L, Tesniere A, et al. Activation of the NLRP3 inflam-masome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. Nat Med 2009; 15:1170-1178.
138. Mucida D, Husain MM, Muroi S, et al. Transcriptional reprogramming of mature CD4(+) helper T cells generates distinct MHC class II-restricted cytotoxic T lymphocytes. Nat Immunol 2013; 14:281-289.
139. Cheroutre H. Starting at the beginning: new perspectives on the biology of mucosal T cells. Annu Rev Immunol 2004; 22:217-246.
140. Coombes JL, Maloy KJ. Control of intestinal homeostasis by regulatory T cells and dendritic cells. Semin Immunol 2007; 19:116-126.
141. Esplugues E, Huber S, Gagliani N, et al. Control of T(H)17 cells occurs in the small intestine. Nature 2011; 475:514-518.
142. Littman DR, Rudensky AY. Th17 and regulatory T cells in mediating and restraining inflammation. Cell 2010; 140:845-858.
143. Maloy KJ. The interleukin-23 /interleukin-17 axis in intestinal inflammation. J Intern Med 2008; 263:584-590.
144. Dubinsky MC, Wang D, Picornell Y, et al. IL-23 receptor (IL-23R) gene protects against pediatric Crohn's disease. Inflamm Bowel Dis 2007; 13:511-515.
145. Duerr RH, Taylor KD, Brant SR, et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 2006; 314:1461-1463.
146. Rioux JD, Xavier RJ, Taylor KD, et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet 2007; 39:596-604.
147. Terzic J, Grivennikov S, Karin E, Karin M. Inflammation and colon cancer. Gastroenterology 2010; 138:2101-2114; e2105.
148. Khazaie K, Blatner NR, Khan MW, et al. The significant role of mast cells in cancer. Cancer Metastasis Revi 2011; 30:45-60.
149. Blatner NR, Mulcahy MF, Dennis KL, et al. Expression of RORgammat marks a pathogenic regulatory T cell subset in human colon cancer. Sci Transl Med 2012; 4:164ra159.
150. Tosolini M, Kirilovsky A, Mlecnik B, et al. Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer. Cancer Res 2011; 71:1263-1271.
151. Marten K, Bremer C, Khazaie K, et al. Detection of dysplastic intestinal adenomas using enzyme-sensing molecular beacons in mice. Gastroenter-ology 2002; 122:406-414.
152. Gounaris E, Erdman SE, Restaino C, et al. Mast cells are an essential hematopoietic component for polyp development. Proc Natl Acad Sci U S A 2007; 104:19977-19982.
153. Gounaris E, Tung CH, Restaino C, et al. Live imaging of cysteine-cathepsin activity reveals dynamics of focal inflammation, angiogenesis, and polyp growth. PLoS One 2008; 3:e2916.
154. Puppa MJ, White JP, Sato S, et al. Gut barrier dysfunction in the Apc(Min/+) mouse model of colon cancer cachexia. Biochim Biophysica Acta 2011; 1812:1601-1606.
155. Grivennikov SI, Wang K, Mucida D, et al. Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Nature 2012; 491:254-258.
156. Gounaris E, Blatner NR, Dennis K, et al. T-regulatory cells shift from a protective anti-inflammatory to a cancer-promoting proinflammatory pheno-type in polyposis. Cancer Res 2009; 69:5490-5497.
157. Khazaie K, Zadeh M, Khan MW, et al. Abating colon cancer polyposis by Lactobacillus acidophilus deficient in lipoteichoic acid. Proc Natl Acad Sci U S A 2012; 109:10462-10467.
158. Huber S, Gagliani N, Esplugues E, et al. Th17 cells express interleukin-10 receptor and are controlled by Foxp3(-) and Foxp3+ regulatory CD4+ T cells in an interleukin-10-dependent manner. Immunity 2011; 34:554-565.
159. Chaudhry A, Samstein RM, Treuting P, et al. Interleukin-10 signaling in regulatory T cells is required for suppression of Th17 cell-mediated inflammation. Immunity 2011; 34:566-578.
160. Rubtsov YP, Rasmussen JP, Chi EY, et al. Regulatory T cell-derived inter-leukin-10 limits inflammation at environmental interfaces. Immunity 2008; 28:546-558.
161. Erdman SE, Poutahidis T, Tomczak M, et al. CD4+ CD25+ regulatory T lymphocytes inhibit microbially induced colon cancer in Rag2-deficient mice. Am J Pathol 2003; 162:691-702.
162. Asseman C, Mauze S, Leach MW, et al. An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J Exp Med 1999; 190:995-1004.
163. Erdman SE, Sohn JJ, Rao VP, et al. CD4+CD25+ regulatory lymphocytes induce regression of intestinal tumors in ApcMin/+ mice. Cancer Res 2005; 65:3998-4004.
164. Correale P, Rotundo MS, Del Vecchio MT, et al. Regulatory (FoxP3+) T-cell tumor infiltration is a favorable prognostic factor in advanced colon cancer patients undergoing chemo or chemoimmunotherapy. J Immunother 2010; 33:435-441.
165. Tougeron D, Maby P, Elie N, et al. T lymphocytes are associated with less aggressive histologic features in microsatellite-unstable colorectal cancers. PLoS One 2013; 8:e61001.
166. Frey DM, Droeser RA, Viehl CT, et al. High frequency of tumor-infiltrating FOXP3(+) regulatory T cells predicts improved survival in mismatch repair-proficient colorectal cancer patients. Int J Cancer 2010; 126:2635-2643.
167. Nosho K, Baba Y, Tanaka N, et al. Tumour-infiltrating T-cell subsets, molecular changes in colorectal cancer, and prognosis: cohort study and literature review. J Pathol 2010; 222:350-366.
168. Salama P, Phillips M, Grieu F, et al. Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol 2009; 27:186-192.
169. Haas M, Dimmler A, Hohenberger W, et al. Stromal regulatory T-cells are associated with a favourable prognosis in gastric cancer of the cardia. BMC Gastroenterol 2009; 9:65.
170. Badoual C, Hans S, Rodriguez J, et al. Prognostic value of tumor-infiltrating CD4+ T-cell subpopulations in head and neck cancers. Clin Cancer Res 2006; 12:465-472.
171. Loose D, Signore A, Bonanno E, et al. Prognostic value of CD25 expression on lymphocytes and tumor cells in squamous-cell carcinoma of the head and neck. Cancer Biother Radiopharm 2008; 23:25-33.
172. Ladoire S, Arnould L, Mignot G, et al. Presence of Foxp3 expression in tumor cells predicts better survival in HER2-overexpressing breast cancer patients treated with neoadjuvant chemotherapy. Breast Cancer Res Treat 2011; 125:65-72.
173. Harrington LE, Hatton RD, Mangan PR, 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.
174. Park H, Li Z, Yang XO, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 2005; 6:1133-1141.
175. Cao AT, Yao S, Gong B, et al. Th17 cells upregulate polymeric Ig receptor and intestinal IgA and contribute to intestinal homeostasis. J Immunol 2012; 189:4666-4673.
176. Ivanov II, McKenzie BS, Zhou L, et al. The orphan nuclear receptor ROR-gammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 2006; 126:1121-1133.
177. Yang XO, Pappu BP, Nurieva R, et al. T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity 2008; 28:29-39.
178. Lebson L, Gocke A, Rosenzweig J, et al. Cutting edge: the transcription factor Kruppel-like factor 4 regulates the differentiation of Th17 cells independently of RORgammat. J Immunol 2010; 185:7161-7164.
179. Kamanaka M, Kim ST, Wan YY, et al. Expression of interleukin-10 in intestinal lymphocytes detected by an interleukin-10 reporter knockin tiger mouse. Immunity 2006; 25:941-952.
180. Peggs KS, Quezada SA, Allison JP. Cell intrinsic mechanisms of T-cell inhibition and application to cancer therapy. Immunol Rev 2008; 224:141-165.
181. Kavanagh B, O'Brien S, Lee D, et al. CTLA4 blockade expands FoxP3+ regulatory and activated effector CD4+ T cells in a dose-dependent fashion. Blood 2008; 112:1175-1183.
182. Coquerelle C, Oldenhove G, Acolty V, et al. Anti-CTLA-4 treatment induces IL-10-producing ICOS+ regulatory T cells displaying IDO-dependent anti-inflammatory properties in a mouse model of colitis. Gut 2009; 58:1363-1373.
183. Chen H, Liakou CI, Kamat A, et al. Anti-CTLA-4 therapy results in higher CD4+ICOShi T cell frequency and IFN-gamma levels in both nonmalignant and malignant prostate tissues. Proc Natl Acad Sci U S A 2009; 106:2729-2734.
184. 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.
185. Pot C, Jin H, Awasthi A, et al. Cutting edge: IL-27 induces the transcription factor c-Maf, cytokine IL-21, and the costimulatory receptor ICOS that coordinately act together to promote differentiation of IL-10-producing Tr1 cells. J Immunol 2009; 183:797-801.
186. Ito T, Hanabuchi S, Wang YH, et al. Two functional subsets of FOXP3+ regulatory T cells in human thymus and periphery. Immunity 2008; 28:870-880.