Selective expansion of allogeneic regulatory T cells by hepatic stellate cells: Role of endotoxin and implications for allograft tolerance

Journal of Immunology

Volumn 188, Issue 8, 2012, Pages 3667-3677

  Dangi, Anil ^a   Sumpter, Tina L ^b   Kimura, Shoko ^a   Stolz, Donna B ^b   Murase, Noriko ^a   Raimondi, Giorgio ^a   Vodovotz, Yoram ^a   Huang, Chao ^a   Thomson, Angus W ^a,b   Gandhi, Chandrashekhar R ^a,b,c  

^a UNIVERSITY OF PITTSBURGH MEDICAL CENTER   (United States)

^b UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

^c VETERANS AFFAIRS MEDICAL CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

B7 ANTIGEN; CD4 ANTIGEN; CD86 ANTIGEN; FAS ANTIGEN; FAS LIGAND; INTERLEUKIN 10; INTERLEUKIN 1ALPHA; INTERLEUKIN 1BETA; INTERLEUKIN 2 RECEPTOR ALPHA; INTERLEUKIN 6; LIPOPOLYSACCHARIDE; MAJOR HISTOCOMPATIBILITY ANTIGEN CLASS 2; TRANSCRIPTION FACTOR FOXP3; TUMOR NECROSIS FACTOR ALPHA;

ALLOGRAFT; ANIMAL CELL; ANIMAL EXPERIMENT; ANTIGEN EXPRESSION; APOPTOSIS; ARTICLE; CD4+ CD25+ FOXP3+ T LYMPHOCYTE; CD4+ T LYMPHOCYTE; CELL ADHESION; CELL MIGRATION; CELL STIMULATION; COCULTURE; CONTROLLED STUDY; CYTOKINE PRODUCTION; IMMUNOLOGICAL TOLERANCE; IN VITRO STUDY; LIVER GRAFT; LYMPH NODE; LYMPHOCYTE PROLIFERATION; LYMPHOID TISSUE; MALE; MOUSE; NONHUMAN; PRIORITY JOURNAL; REGULATORY T LYMPHOCYTE; STELLATE CELL;

ADOPTIVE TRANSFER; ANIMALS; ANTIGENS, CD; APOPTOSIS; CELL COMMUNICATION; CELL PROLIFERATION; CELLS, CULTURED; CYTOKINES; ENDOTOXINS; GENE EXPRESSION REGULATION; GENES, MHC CLASS II; HEPATIC STELLATE CELLS; LIVER TRANSPLANTATION; LYMPH NODES; LYMPHOCYTE ACTIVATION; MICE; MICE, INBRED BALB C; SIGNAL TRANSDUCTION; T-LYMPHOCYTES, REGULATORY; TRANSCRIPTION FACTORS; TRANSPLANTATION TOLERANCE; TRANSPLANTATION, HOMOLOGOUS;

EID: 84860318483     PISSN: 00221767     EISSN: 15506606     Source Type: Journal    
DOI: 10.4049/jimmunol.1102460     Document Type: Article

References (77)

1. Crispe, I. N. 2009. The liver as a lymphoid organ. Annu. Rev. Immunol. 27: 147-163.
2. Thomson, A. W., and P. A. Knolle. 2010. Antigen-presenting cell function in the tolerogenic liver environment. Nat. Rev. Immunol. 10: 753-766.
3. Calne, R. Y., R. A. Sells, J. R. Pena, D. R. Davis, P. R. Millard, B. M. Herbertson, R. M. Binns, and D. A. Davies. 1969. Induction of immunological tolerance by porcine liver allografts. Nature 223: 472-476.
4. Sun, J., A. G. Sheil, C. Wang, L. Wang, K. Rokahr, A. Sharland, S. E. Jung, L. Li, G. W. McCaughan, and G. A. Bishop. 1996. Tolerance to rat liver allografts: IV. Acceptance depends on the quantity of donor tissue and on donor leukocytes. Transplantation 62: 1725-1730.
5. Pons, J. A., B. Revilla-Nuin, A. Baroja-Mazo, P. Ramírez, L. Martínez-Alarcón, F. S ánchez-Bueno, R. Robles, A. Rios, P. Aparicio, and P. Parrilla. 2008. FoxP3 in peripheral blood is associated with operational tolerance in liver transplant patients during immunosuppression withdrawal. Transplantation 86: 1370-1378.
6. Castellaneta, A., A. W. Thomson, N. Nayyar, M. de Vera, and G. V. Mazariegos. 2010. Monitoring the operationally tolerant liver allograft recipient. Curr. Opin. Organ Transplant. 15: 28-34.
7. Kreisel, D., H. Petrowsky, A. M. Krasinskas, A. S. Krupnick, W. Y. Szeto, A. D. McLean, S. H. Popma, A. E. Gelman, M. K. Traum, E. E. Furth, et al. 2002. The role of passenger leukocyte genotype in rejection and acceptance of rat liver allografts. Transplantation 73: 1501-1507. (Pubitemid 34552233)
8. Bishop, G. A., C. Wang, A. F. Sharland, and G. McCaughan. 2002. Spontaneous acceptance of liver transplants in rodents: evidence that liver leucocytes induce recipient T-cell death by neglect. Immunol. Cell Biol. 80: 93-100. (Pubitemid 34415538)
9. Araújo, M. B., L. S. Leonardi, M. I. Leonardi, I. F. Boin, L. A. Magna, E. A. Donadi, and M. H. Kraemer. 2009. Prospective analysis between the therapy of immunosuppressive medication and allogeneic microchimerism after liver transplantation. Transpl. Immunol. 20: 195-198.
10. Knechtle, S. J., and J. Kwun. 2009. Unique aspects of rejection and tolerance in liver transplantation. Semin. Liver Dis. 29: 91-101.
11. Tiegs, G., and A. W. Lohse. 2010. Immune tolerance: what is unique about the liver. J. Autoimmun. 34: 1-6.
12. Friedman, S. L. 2000. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J. Biol. Chem. 275: 2247-2250. (Pubitemid 30081976)
13. Geerts, A. 2001. History, heterogeneity, developmental biology, and functions of quiescent hepatic stellate cells. Semin. Liver Dis. 21: 311-335. (Pubitemid 32923763)
14. Gandhi, C. R. 2010. Stellate cells. In Molecular Pathology of Liver Diseases. Molecular Pathology Library, Part 1. S. P. Monga, ed. Springer, New York, p. 53-80.
15. Marra, F. 1999. Hepatic stellate cells and the regulation of liver inflammation. J. Hepatol. 31: 1120-1130.
16. Pinzani, M., and F. Marra. 2001. Cytokine receptors and signaling in hepatic stellate cells. Semin. Liver Dis. 21: 397-416. (Pubitemid 32923768)
17. Yu, M. C., C. H. Chen, X. Liang, L. Wang, C. R. Gandhi, J. J. Fung, L. Lu, and S. Qian. 2004. Inhibition of T-cell responses by hepatic stellate cells via B7-H1mediated T-cell apoptosis in mice. Hepatology 40: 1312-1321. (Pubitemid 39657005)
18. Winau, F., G. Hegasy, R. Weiskirchen, S. Weber, C. Cassan, P. A. Sieling, R. L. Modlin, R. S. Liblau, A. M. Gressner, and S. H. Kaufmann. 2007. Ito cells are liver-resident antigen-presenting cells for activating T cell responses. Immunity 26: 117-129. (Pubitemid 46109346)
19. Jiang, G., H. R. Yang, L. Wang, G. M. Wildey, J. J. Fung, S. Qian, and L. Lu. 2008. Hepatic stellate cells preferentially expand allogeneic CD4+ CD25+ FoxP3+ regulatory T cells in an IL-2-dependent manner. Transplantation 86: 1492-1502.
20. Schildberg, F. A., C. Kurts, and P. A. Knolle. 2011. Prominent regulatory but weak antigen-presenting cell function of hepatic stellate cells. Hepatology 54: 1108.
21. Schildberg, F. A., A. Wojtalla, S. V. Siegmund, E. Endl, L. Diehl, Z. Abdullah, C. Kurts, and P. A. Knolle. 2011. Murine hepatic stellate cells veto CD8 T cell activation by a CD54-dependent mechanism. Hepatology 54: 262-272.
22. Cheng, F., Y. Li, L. Feng, and S. Li. 2008. Hepatic stellate cell activation and hepatic fibrosis induced by ischemia/reperfusion injury. Transplant. Proc. 40: 2167-2170.
23. Cheng, Q., K. T. Ng, S. T. Fan, Z. X. Lim, D. Y. Guo, X. B. Liu, Y. Liu, R. T. Poon, C. M. Lo, and K. Man. 2010. Distinct mechanism of small-for-size fatty liver graft injury - Wnt4 signaling activates hepatic stellate cells. Am. J. Transplant. 10: 1178-1188.
24. Gao, W., R. C. Bentley, J. F. Madden, and P. A. Clavien. 1998. Apoptosis of sinusoidal endothelial cells is a critical mechanism of preservation injury in rat liver transplantation. Hepatology 27: 1652-1660. (Pubitemid 28264691)
25. Stolz, D. B., M. A. Ross, A. Ikeda, K. Tomiyama, T. Kaizu, D. A. Geller, and N. Murase. 2007. Sinusoidal endothelial cell repopulation following ischemia/ reperfusion injury in rat liver transplantation. Hepatology 46: 1464-1475. (Pubitemid 350155528)
26. Uemura, T., and C. R. Gandhi. 2001. Inhibition of DNA synthesis in cultured hepatocytes by endotoxin-conditioned medium of activated stellate cells is transforming growth factor-β and nitric oxide-independent. Br. J. Pharmacol. 133: 1125-1133. (Pubitemid 32762424)
27. Thirunavukkarasu, C., T. Uemura, L. F. Wang, S. C. Watkins, and C. R. Gandhi. 2005. Normal rat hepatic stellate cells respond to endotoxin in LBP-independent manner to produce inhibitor(s) of DNA synthesis in hepatocytes. J. Cell. Physiol. 204: 654-665. (Pubitemid 40934662)
28. Thirunavukkarasu, C., S. C. Watkins, and C. R. Gandhi. 2006. Mechanisms of endotoxin-induced NO, IL-6, and TNF-alpha production in activated rat hepatic stellate cells: role of p38 MAPK. Hepatology 44: 389-398. (Pubitemid 44214878)
29. Miyata, T., I. Yokoyama, S. Todo, A. Tzakis, R. Selby, and T. E. Starzl. 1989. Endotoxaemia, pulmonary complications, and thrombocytopenia in liver transplantation. Lancet 2: 189-191. (Pubitemid 19186999)
30. Mehal, W. Z., A. E. Juedes, and I. N. Crispe. 1999. Selective retention of activated CD8+ T cells by the normal liver. J. Immunol. 163: 3202-3210. (Pubitemid 29431820)
31. Liu, W., A. L. Putnam, Z. Xu-Yu, G. L. Szot, M. R. Lee, S. Zhu, P. A. Gottlieb, P. Kapranov, T. R. Gingeras, B. Fazekas de St Groth, et al. 2006. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J. Exp. Med. 203: 1701-1711. (Pubitemid 44036276)
32. Raimondi, G., T. L. Sumpter, B. M. Matta, M. Pillai, N. Corbitt, Y. Vodovotz, Z. Wang, and A. W. Thomson. 2010. Mammalian target of rapamycin inhibition and alloantigen-specific regulatory T cells synergize to promote long-term graft survival in immunocompetent recipients. J. Immunol. 184: 624-636.
33. Klugewitz, K., D. H. Adams, M. Emoto, K. Eulenburg, and A. Hamann. 2004. The composition of intrahepatic lymphocytes: shaped by selective recruitment? Trends Immunol. 25: 590-594. (Pubitemid 39369735)
34. Bowen, D. G., G. W. McCaughan, and P. Bertolino. 2005. Intrahepatic immunity: a tale of two sites? Trends Immunol. 26: 512-517. (Pubitemid 41297680)
35. McAleer, J. P., R. J. Rossi, and A. T. Vella. 2009. Lipopolysaccharide potentiates effector T cell accumulation into nonlymphoid tissues through TRIF. J. Immunol. 182: 5322-5330.
36. Maksimow, M., T. S. Söderström, S. Jalkanen, J. E. Eriksson, and A. Hänninen. 2006. Fas costimulation of naive CD4 T cells is controlled by NF-kappaB signaling and caspase activity. J. Leukoc. Biol. 79: 369-377. (Pubitemid 44831169)
37. Francisco, L. M., V. H. Salinas, K. E. Brown, V. K. Vanguri, G. J. Freeman, V. K. Kuchroo, and A. H. Sharpe. 2009. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J. Exp. Med. 206: 3015-3029.
38. Keir, M. E., M. J. Butte, G. J. Freeman, and A. H. Sharpe. 2008. PD-1 and its ligands in tolerance and immunity. Annu. Rev. Immunol. 26: 677-704. (Pubitemid 351600389)
39. Kinter, A. L., E. J. Godbout, J. P. McNally, I. Sereti, G. A. Roby, M. A. O'Shea, and A. S. Fauci. 2008. The common gamma-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands. J. Immunol. 181: 6738-6746.
40. Thornton, A. M., P. E. Korty, D. Q. Tran, E. A. Wohlfert, P. E. Murray, Y. Belkaid, and E. M. Shevach. 2010. Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J. Immunol. 184: 3433-3441.
41. Mucida, D., Y. Park, G. Kim, O. Turovskaya, I. Scott, M. Kronenberg, and H. Cheroutre. 2007. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317: 256-260. (Pubitemid 47076203)
42. Lau, A. W., S. Biester, R. J. Cornall, and J. V. Forrester. 2008. Lipopolysaccharide-activated IL-10-secreting dendritic cells suppress experimental autoimmune uveoretinitis by MHCII-dependent activation of CD62Lexpressing regulatory T cells. J. Immunol. 180: 3889-3899.
43. Darrasse-Jèze, G., S. Deroubaix, H. Mouquet, G. D. Victora, T. Eisenreich, K. H. Yao, R. F. Masilamani, M. L. Dustin, A. Rudensky, K. Liu, and M. C. Nussenzweig. 2009. Feedback control of regulatory T cell homeostasis by dendritic cells in vivo. J. Exp. Med. 206: 1853-1862.
44. Zou, T., A. J. Caton, G. A. Koretzky, and T. Kambayashi. 2010. Dendritic cells induce regulatory T cell proliferation through antigen-dependent and -independent interactions. J. Immunol. 185: 2790-2799.
45. Liao, G., S. Nayak, J. R. Regueiro, S. B. Berger, C. Detre, X. Romero, R. de Waal Malefyt, T. A. Chatila, R. W. Herzog, and C. Terhorst. 2010. GITR engagement preferentially enhances proliferation of functionally competent CD4+ CD25+FoxP3+ regulatory T cells. Int. Immunol. 22: 259-270.
46. Read, S., R. Greenwald, A. Izcue, N. Robinson, D. Mandelbrot, L. Francisco, A. H. Sharpe, and F. Powrie. 2006. Blockade of CTLA-4 on CD4+CD25+ regulatory T cells abrogates their function in vivo. J. Immunol. 177: 4376-4383. (Pubitemid 44469766)
47. Huang, C. T., C. J. Workman, D. Flies, X. Pan, A. L. Marson, G. Zhou, E. L. Hipkiss, S. Ravi, J. Kowalski, H. I. Levitsky, et al. 2004. Role of LAG-3 in regulatory T cells. Immunity 21: 503-513. (Pubitemid 39370506)
48. Huehn, J., K. Siegmund, J. C. Lehmann, C. Siewert, U. Haubold, M. Feuerer, G. F. Debes, J. Lauber, O. Frey, G. K. Przybylski, et al. 2004. Developmental stage, phenotype, and migration distinguish naive- and effector/memory-like CD4+ regulatory T cells. J. Exp. Med. 199: 303-313. (Pubitemid 38252043)
49. Rudensky, A. Y. 2011. Regulatory T cells and Foxp3. Immunol. Rev. 241: 260-268.
50. Li, W., C. S. Kuhr, X. X. Zheng, K. Carper, A. W. Thomson, J. D. Reyes, and J. D. Perkins. 2008. New insights into mechanisms of spontaneous liver transplant tolerance: the role of Foxp3-expressing CD25+CD4+ regulatory T cells. Am. J. Transplant. 8: 1639-1651.
51. Bertolino, P., M. C. Trescol-Biémont, J. Thomas, B. Fazekas de St Groth, M. Pihlgren, J. Marvel, and C. Rabourdin-Combe. 1999. Death by neglect as a deletional mechanism of peripheral tolerance. Int. Immunol. 11: 1225-1238.
52. Hellerbrand, S. C., S. C. Wang, H. Tsukamoto, D. A. Brenner, and R. A. Rippe. 1996. Expression of intracellular adhesion molecule 1 by activated hepatic stellate cells. Hepatology 24: 670-676. (Pubitemid 26296014)
53. Knittel, T., C. Dinter, D. Kobold, K. Neubauer, M. Mehde, S. Eichhorst, and G. Ramadori. 1999. Expression and regulation of cell adhesion molecules by hepatic stellate cells (HSC) of rat liver: involvement of HSC in recruitment of inflammatory cells during hepatic tissue repair. Am. J. Pathol. 154: 153-167. (Pubitemid 29031623)
54. Aziz-Seible, R. S., and C. A. Casey. 2011. Fibronectin: functional character and role in alcoholic liver disease. World J. Gastroenterol. 17: 2482-2499.
55. Moore, C., X. D. Shen, C. Fondevila, F. Gao, and A. J. Coito. 2005. Blockade of fibronectin-alpha4beta1 adhesive interactions down-regulates cyclooxygenase-2 inducible nitric oxide synthase and prolongs recipient survival in a 24-hour model of cold hepatic ischemia-reperfusion injury. Transplant. Proc. 37: 1682-1683. (Pubitemid 40790794)
56. Hill, J. A., J. A. Hall, C. M. Sun, Q. Cai, N. Ghyselinck, P. Chambon, Y. Belkaid, D. Mathis, and C. Benoist. 2008. Retinoic acid enhances Foxp3 induction indirectly by relieving inhibition from CD4+CD44hi Cells. Immunity 29: 758-770.
57. Zhai, Y., X. D. Shen, W. W. Hancock, F. Gao, B. Qiao, C. Lassman, J. A. Belperio, R. M. Strieter, R. W. Busuttil, and J. W. Kupiec-Weglinski. 2006. CXCR3+CD4+ T cells mediate innate immune function in the pathophysiology of liver ischemia/reperfusion injury. J. Immunol. 176: 6313-6322.
58. Chen, C. H., L. M. Kuo, Y. Chang, W. Wu, C. Goldbach, M. A. Ross, D. B. Stolz, L. Chen, J. J. Fung, L. Lu, and S. Qian. 2006. In vivo immune modulatory activity of hepatic stellate cells in mice. Hepatology 44: 1171-1181. (Pubitemid 44748368)
59. Benten, D., V. Kumaran, B. Joseph, J. Schattenberg, Y. Popov, D. Schuppan, and S. Gupta. 2005. Hepatocyte transplantation activates hepatic stellate cells with beneficial modulation of cell engraftment in the rat. Hepatology 42: 1072-1081. (Pubitemid 43112674)
60. Wiegard, C., C. Frenzel, J. Herkel, K. J. Kallen, E. Schmitt, and A. W. Lohse. 2005. Murine liver antigen presenting cells control suppressor activity of CD4+ CD25+ regulatory T cells. Hepatology 42: 193-199. (Pubitemid 40911327)
61. Paulsen, M., B. Mathew, J. Qian, M. Lettau, D. Kabelitz, and O. Janssen. 2009. FasL cross-linking inhibits activation of human peripheral T cells. Int. Immunol. 21: 587-598.
62. Pender, M. P. 1999. Activation-induced apoptosis of autoreactive and alloreactive T lymphocytes in the target organ as a major mechanism of tolerance. Immunol. Cell Biol. 77: 216-223. (Pubitemid 29251574)
63. Egawa, T., R. E. Tillman, Y. Naoe, I. Taniuchi, and D. R. Littman. 2007. The role of the Runx transcription factors in thymocyte differentiation and in homeostasis of naive T cells. J. Exp. Med. 204: 1945-1957. (Pubitemid 47236329)
64. Wan, Y. Y., and R. A. Flavell. 2007. Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression. Nature 445: 766-770. (Pubitemid 46279706)
65. Knolle, P., J. Schlaak, A. Uhrig, P. Kempf, K. H. Meyerzum Büschenfelde, and G. Gerken. 1995. Human Kupffer cells secrete IL-10 in response to lipopolysaccharide (LPS) challenge. J. Hepatol. 22: 226-229.
66. Groux, H., M. Bigler, J. E. de Vries, and M. G. Roncarolo. 1996. Interleukin-10 induces a long-term antigen-specific anergic state in human CD4+ T cells. J. Exp. Med. 184: 19-29. (Pubitemid 26247211)
67. Knolle, P. A., T. Germann, U. Treichel, A. Uhrig, E. Schmitt, S. Hegenbarth, A. W. Lohse, and G. Gerken. 1999. Endotoxin down-regulates T cell activation by antigen-presenting liver sinusoidal endothelial cells. J. Immunol. 162: 1401-1407. (Pubitemid 29307011)
68. Bamboat, Z. M., J. A. Stableford, G. Plitas, B. M. Burt, H. M. Nguyen, A. P. Welles, M. Gonen, J. W. Young, and R. P. DeMatteo. 2009. Human liver dendritic cells promote T cell hyporesponsiveness. J. Immunol. 182: 1901-1911.
69. Pasare, C., and R. Medzhitov. 2003. Toll pathway-dependent blockade of CD4+ CD25+ T cell-mediated suppression by dendritic cells. Science 299: 1033-1036. (Pubitemid 36222922)
70. Erhardt, A., M. Biburger, T. Papadopoulos, and G. Tiegs. 2007. IL-10, regulatory T cells, and Kupffer cells mediate tolerance in concanavalin A-induced liver injury in mice. Hepatology 45: 475-485. (Pubitemid 46374604)
71. Knolle, P. A., E. Löser, U. Protzer, R. Duchmann, E. Schmitt, K. H. M. zum Büschenfelde, S. Rose-John, and G. Gerken. 1997. Regulation of endotoxininduced IL-6 production in liver sinusoidal endothelial cells and Kupffer cells by IL-10. Clin. Exp. Immunol. 107: 555-561. (Pubitemid 27102146)
72. Irla, M., N. Küpfer, T. Suter, R. Lissilaa, M. Benkhoucha, J. Skupsky, P. H. Lalive, A. Fontana, W. Reith, and S. Hugues. 2010. MHC class II-restricted antigen presentation by plasmacytoid dendritic cells inhibits T cell-mediated autoimmunity. J. Exp. Med. 207: 1891-1905.
73. Kambayashi, T., E. J. Allenspach, J. T. Chang, T. Zou, J. E. Shoag, S. L. Reiner, A. J. Caton, and G. A. Koretzky. 2009. Inducible MHC class II expression by mast cells supports effector and regulatory T cell activation. J. Immunol. 182: 4686-4695.
74. Hombach, A. A., D. Kofler, A. Hombach, G. Rappl, and H. Abken. 2007. Effective proliferation of human regulatory T cells requires a strong costimulatory CD28 signal that cannot be substituted by IL-2. J. Immunol. 179: 7924-7931.
75. Chen, X., and P. E. Jensen. 2007. Cutting edge: primary B lymphocytes preferentially expand allogeneic FoxP3+ CD4 T cells. J. Immunol. 179: 2046-2050.
76. Bamboat, Z. M., L. M. Ocuin, V. P. Balachandran, H. Obaid, G. Plitas, and R. P. DeMatteo. 2010. Conventional DCs reduce liver ischemia/reperfusion injury in mice via IL-10 secretion. J. Clin. Invest. 120: 559-569.
77. Ochando, J. C., A. C. Yopp, Y. Yang, A. Garin, Y. Li, P. Boros, J. Llodra, Y. Ding, S. A. Lira, N. R. Krieger, and J. S. Bromberg. 2005. Lymph node occupancy is required for the peripheral development of alloantigen-specific Foxp3+ regulatory T cells. J. Immunol. 174: 6993-7005. (Pubitemid 40705664)