CD8+ Tregs in lupus, autoimmunity, and beyond

Autoimmunity Reviews

Volumn 9, Issue 8, 2010, Pages 560-568

  Dinesh, Ravi K ^a   Skaggs, Brian J ^a   La Cava, Antonio ^a   Hahn, Bevra H ^a   Singh, Ram Pyare ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

Autoimmunity; CD8+ Tregs; Immune tolerance suppression; Systemic lupus erythematosus

Indexed keywords

CD103 ANTIGEN; CD27 ANTIGEN; CD28 ANTIGEN; CD45RO ANTIGEN; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; GAMMA INTERFERON; GLATIRAMER; INTERLEUKIN 10; INTERLEUKIN 16; INTERLEUKIN 17; INTERLEUKIN 2 RECEPTOR BETA; L SELECTIN; MACROPHAGE INFLAMMATORY PROTEIN 1BETA; PROGRAMMED DEATH 1 RECEPTOR; TRANSCRIPTION FACTOR FOXP3; TRANSFORMING GROWTH FACTOR BETA;

ALLERGIC ENCEPHALOMYELITIS; AUTOIMMUNITY; AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION; CD4+ CD25+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; COLORECTAL CANCER; CROHN DISEASE; CYTOKINE RELEASE; HEPATITIS C; HERPES SIMPLEX; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; IMMUNOLOGICAL TOLERANCE; INSULIN DEPENDENT DIABETES MELLITUS; MULTIPLE SCLEROSIS; MYASTHENIA GRAVIS; NONHUMAN; NONOBESE DIABETIC MOUSE; PROSTATE CANCER; REGULATORY T LYMPHOCYTE; REVIEW; RHEUMATOID ARTHRITIS; SYSTEMIC LUPUS ERYTHEMATOSUS; ULCERATIVE COLITIS;

ANIMALS; AUTOIMMUNITY; CD8-POSITIVE T-LYMPHOCYTES; HUMANS; LUPUS ERYTHEMATOSUS, SYSTEMIC; MICE; T-LYMPHOCYTE SUBSETS; T-LYMPHOCYTES, REGULATORY;

EID: 77952743515     PISSN: 15689972     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.autrev.2010.03.006     Document Type: Review

References (150)

1. Gershon R.K., and Kondo K. Cell interactions in the induction of tolerance: the role of thymic lymphocytes. Immunology 18 (1970) 723-737
2. Baker P.J., Stashak P.W., Amsbaugh D.F., Prescott B., and Barth R.F. Evidence for the existence of two functionally distinct types of cells which regulate the antibody response to type 3 pneumococcal polysaccharide. J Immunol 105 (1970) 1581-1583
3. Barth R.F., Singla O., and Liu C. Suppressor T cells and host resistance to type III pneumococcus after treatment with antilymphocyte serum. Infect Immun 12 (1975) 1307-1312
4. Cantor H., Shen F.W., and Boyse E.A. Separation of helper T cells from suppressor T cells expressing different Ly components. II. Activation by antigen: after immunization, antigen-specific suppressor and helper activities are mediated by distinct T-cell subclasses. J Exp Med 143 (1976) 1391-40
5. Cantor H., Hugenberger J., McVay-Boudreau L., Eardley D.D. K.J., Shen F.W., et al. Immunoregulatory circuits among T-cell sets. Identification of a subpopulation of T-helper cells that induces feedback inhibition. J Exp Med 148 (1978) 871-877
6. Eardley D.D., Hugenberger J., McVay-Boudreau L., Shen F.W., Gershon R.K., and Cantor H. Immunoregulatory circuits among T-cell sets. I. T-helper cells induce other T-cell sets to exert feedback inhibition. J Exp Med 147 (1978) 1106-1115
7. Sakaguchi S., Sakaguchi N., Asano M., Itoh M., and 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 155 (1995) 1151-1164
8. Sakaguchi S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 6 (2005) 345-352
9. Valencia X., Yarboro C., Illei G., and Lipsky P.E. Deficient CD4+CD25high T regulatory cell function in patients with active systemic lupus erythematosus. J Immunol 178 (2007) 2579-2588
10. Banham A.H., Powrie F.M., and Suri-Payer E. FOXP3+ regulatory T cells: current controversies and future perspectives. Eur J Immunol 36 (2006) 2832-2836
11. Cools N., Ponsaerts P., Van Tendeloo V.F., and Berneman Z.N. Regulatory T cells and human disease. Clin Dev Immunol (2007) 89195
12. Tang X.L., Smith T.R., and Kumar V. Specific control of immunity by regulatory CD8 T cells. Cell Mol Immunol 2 (2005) 11-19
13. Bouaziz J.D., Yanaba K., and Tedder T.F. Regulatory B cells as inhibitors of immune responses and inflammation. Immunol Rev 224 (2008) 201-214
14. Lemoine S., Morva A., Youinou P., and Jamin C. Regulatory B cells in autoimmune diseases: how do they work?. Ann N Y Acad Sci 1173 (2009) 260-267
15. La Cava A. T-regulatory cells in systemic lupus erythematosus. Lupus 17 (2008) 421-425
16. Sakaguchi S., Yamaguchi T., Nomura T., and Ono M. Regulatory T cells and immune tolerance. Cell 133 (2008) 775-787
17. Suzuki M., Konya C., Goronzy J.J., and Weyand C.M. Inhibitory CD8+ T cells in autoimmune disease. Hum Immunol 69 (2008) 781-789
18. Billerbeck E., and Thimme R. CD8+ regulatory T cells in persistent human viral infections. Hum Immunol 69 (2008) 771-775
19. Wang H.Y., and Wang R.F. Regulatory T cells and cancer. Curr Opin Immunol 19 (2007) 217-223
20. Joosten S.A., and Ottenhoff T.H. Human CD4 and CD8 regulatory T cells in infectious diseases and vaccination. Hum Immunol 69 (2008) 760-770
21. Curiel T.J. Tregs and rethinking cancer immunotherapy. J Clin Invest 117 (2007) 1167-1174
22. Walsh P.T., Taylor D.K., and Turka L.A. Tregs and transplantation tolerance. J Clin Invest 114 (2004) 1398-1403
23. Costantino C.M., Baecher-Allan C.M., and Hafler D.A. Human regulatory T cells and autoimmunity. Eur J Immunol 38 (2008) 921-924
24. Kang H.K., and Datta S.K. Regulatory T cells in lupus. Int Rev Immunol 25 (2006) 5-25
25. Cosmi L., Liotta F., Lazzeri E., Francalanci M., Angeli R., Mazzinghi B., et al. Human CD8+CD25+ thymocytes share phenotypic and functional features with CD4+CD25+ regulatory thymocytes. Blood 102 (2003) 4107-4114
26. Suzuki H., Kundig T.M., Furlonger C., Wakeham A., Timms E., Matsuyama T., et al. Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor beta. Science 268 (1995) 1472-1476
27. Rifa'i M., Kawamoto Y., Nakashima I., and Suzuki H. Essential roles of CD8+CD122+ regulatory T cells in the maintenance of T cell homeostasis. J Exp Med 200 (2004) 1123-1134
28. Shi Z., Okuno Y., Rifa'i M., Endharti A.T., Akane K., Isobe K., et al. Human CD8+CXCR3+ T cells have the same function as murine CD8+CD122+ Treg. Eur J Immunol 39 (2009) 2106-2119
29. Uss E., Rowshani A.T., Hooibrink B., Lardy N.M., van Lier R.A., and ten Berge I.J. CD103 is a marker for alloantigen-induced regulatory CD8+ T cells. J Immunol 177 (2006) 2775-2783
30. Billerbeck E., Blum H.E., and Thimme R. Parallel expansion of human virus-specific FoxP3- effector memory and de novo-generated FoxP3+ regulatory CD8+ T cells upon antigen recognition in vitro. J Immunol 179 (2007) 1039-1048
31. Lu L., Yu Y., Li G., Pu L., Zhang F., Zheng S., et al. CD8(+)CD103 (+) regulatory T cells in spontaneous tolerance of liver allografts. Int Immunopharmacol 9 (2009) 546-548
32. Zhou J., Appleton S.E., Stadnyk A., Lee T.D., and Nashan B.A. CD8+ gammadelta T regulatory cells mediate kidney allograft prolongation after oral exposure to alloantigen. Transpl Int 21 (2008) 679-687
33. Ciubotariu R., Colovai A.I., Pennesi G., Liu Z., Smith D., Berlocco P., et al. Specific suppression of human CD4+ Th cell responses to pig MHC antigens by CD8+CD28- regulatory T cells. J Immunol 161 (1998) 5193-5202
34. Liu Z., Tugulea S., Cortesini R., and Suciu-Foca N. Specific suppression of T helper alloreactivity by allo-MHC class I-restricted CD8+CD28- T cells. Int Immunol 10 (1998) 775-783
35. Filaci G., Fravega M., Negrini S., Procopio F., Fenoglio D., Rizzi M., et al. Nonantigen specific CD8+ T suppressor lymphocytes originate from CD8+CD28- T cells and inhibits both T-cell proliferation and CTL function. Hum Immunol 65 (2004) 142-156
36. Filaci G., Rizzi M., Setti M., Fenoglio D., Fravega M., Basso M., et al. Non-antigen-specific CD8 (+) T suppressor lymphocytes in diseases characterized by chronic immune responses and inflammation. Ann N Y Acad Sci 1050 (2005) 115-123
37. Mahic M., Henjum K., Yaqub S., Bjornbeth B.A., Torgersen K.M., Tasken K., et al. Generation of highly suppressive adaptive CD8 (+) CD25 (+) FOXP3 (+) regulatory T cells by continuous antigen stimulation. Eur J Immunol 38 (2008) 640-646
38. Jarvis L.B., Matyszak M.K., Duggleby R.C., Goodall J.C., Hall F.C., and Gaston J.S. Autoreactive human peripheral blood CD8+ T cells with a regulatory phenotype and function. Eur J Immunol 35 (2005) 2896-2908
39. Joosten S.A., van Meijgaarden K.E., Savage N.D., de Boer T., Triebel F., van der Wal A., et al. Identification of a human CD8+ regulatory T cell subset that mediates suppression through the chemokine CC chemokine ligand 4. Proc Natl Acad Sci U S A 104 (2007) 8029-8034
40. Wei S., Kryczek I., Zou L., Daniel B., Cheng P., Mottram P., et al. Plasmacytoid dendritic cells induce CD8+ regulatory T cells in human ovarian carcinoma. Cancer Res 65 (2005) 5020-5026
41. Gilliet M., and Liu Y.J. Generation of human CD8 T regulatory cells by CD40 ligand-activated plasmacytoid dendritic cells. J Exp Med 195 (2002) 695-704
42. Zheng J., Liu Y., Qin G., Chan P.L., Mao H., Lam K.T., et al. Efficient induction and expansion of human alloantigen-specific CD8 regulatory T cells from naive precursors by CD40-activated B cells. J Immunol 183 (2009) 3742-3750
43. Dhodapkar M.V., and Steinman R.M. Antigen-bearing immature dendritic cells induce peptide-specific CD8 (+) regulatory T cells in vivo in humans. Blood 100 (2002) 174-177
44. He H., Yang P., Jiang L., Zhang J., Zhao C., Chen L., et al. Upregulation of CD94 on CD8+ T cells in anterior chamber-associated immune deviation. BMC Immunol 9 (2008) 53
45. La Cava A. Tregs are regulated by cytokines: implications for autoimmunity. Autoimmun Rev 8 (2008) 83-87
46. Bisikirska B., Colgan J., Luban J., Bluestone J.A., and Herold K.C. TCR stimulation with modified anti-CD3 mAb expands CD8+ T cell population and induces CD8+CD25+ Tregs. J Clin Invest 115 (2005) 2904-2913
47. Singh R.P., La Cava A., Wong M., Ebling F., and Hahn B.H. CD8+ T cell-mediated suppression of autoimmunity in a murine lupus model of peptide-induced immune tolerance depends on Foxp3 expression. J Immunol 178 (2007) 7649-7657
48. Singh R.P., La Cava A., and Hahn B.H. pConsensus peptide induces tolerogenic CD8+ T cells in lupus-prone (NZB x NZW)F1 mice by differentially regulating Foxp3 and PD1 molecules. J Immunol 180 (2008) 2069-2080
49. Hahn B.H., Singh R.P., La Cava A., and Ebling F.M. Tolerogenic treatment of lupus mice with consensus peptide induces Foxp3-expressing, apoptosis-resistant, TGFbeta-secreting CD8+ T cell suppressors. J Immunol 175 (2005) 7728-7737
50. Allan S.E., Crome S.Q., Crellin N.K., Passerini L., Steiner T.S., Bacchetta R., et al. Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production. Int Immunol 19 (2007) 345-354
51. Wang J., Ioan-Facsinay A., van der Voort E.I., Huizinga T.W., and Toes R.E. Transient expression of FOXP3 in human activated nonregulatory CD4+ T cells. Eur J Immunol 37 (2007) 129-138
52. Pillai V., Ortega S.B., Wang C.K., and Karandikar N.J. Transient regulatory T-cells: a state attained by all activated human T-cells. Clin Immunol 123 (2007) 18-29
53. Zelenay S., Lopes-Carvalho T., Caramalho I., Moraes-Fontes M.F., Rebelo M., and Demengeot J. Foxp3+ CD25- CD4 T cells constitute a reservoir of committed regulatory cells that regain CD25 expression upon homeostatic expansion. Proc Natl Acad Sci U S A 102 (2005) 4091-4096
54. Hinz S., Pagerols-Raluy L., Oberg H.H., Ammerpohl O., Grussel S., Sipos B., et al. Foxp3 expression in pancreatic carcinoma cells as a novel mechanism of immune evasion in cancer. Cancer Res 67 (2007) 8344-8350
55. Zuo T., Wang L., Morrison C., Chang X., Zhang H., Li W., et al. FOXP3 is an X-linked breast cancer suppressor gene and an important repressor of the HER-2/ErbB2 oncogene. Cell 129 (2007) 1275-1286
56. Chen G.Y., Chen C., Wang L., Chang X., Zheng P., and Liu Y. Cutting edge: broad expression of the FoxP3 locus in epithelial cells: a caution against early interpretation of fatal inflammatory diseases following in vivo depletion of FoxP3-expressing cells. J Immunol 180 (2008) 5163-5166
57. Fontenot J.D., Gavin M.A., and Rudensky A.Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4 (2003) 330-336
58. Morgan M.E., van Bilsen J.H., Bakker A.M., Heemskerk B., Schilham M.W., Hartgers F.C., et al. Expression of FOXP3 mRNA is not confined to CD4+CD25+ T regulatory cells in humans. Hum Immunol 66 (2005) 13-20
59. Filaci G., Fravega M., Fenoglio D., Rizzi M., Negrini S., Viggiani R., et al. Non-antigen specific CD8+ T suppressor lymphocytes. Clin Exp Med 4 (2004) 86-92
60. Menager-Marcq I., Pomie C., Romagnoli P., and van Meerwijk J.P. CD8+CD28- regulatory T lymphocytes prevent experimental inflammatory bowel disease in mice. Gastroenterology 131 (2006) 1775-1785
61. Filaci G., Fenoglio D., Fravega M., Ansaldo G., Borgonovo G., Traverso P., et al. CD8+ CD28- T regulatory lymphocytes inhibiting T cell proliferative and cytotoxic functions infiltrate human cancers. J Immunol 179 (2007) 4323-4334
62. Kiniwa Y., Miyahara Y., Wang H.Y., Peng W., Peng G., Wheeler T.M., et al. CD8+ Foxp3+ regulatory T cells mediate immunosuppression in prostate cancer. Clin Cancer Res 13 (2007) 6947-6958
63. Askenasy N., Kaminitz A., and Yarkoni S. Mechanisms of T regulatory cell function. Autoimmun Rev 7 (2008) 370-375
64. Endharti A.T., Shi Z., Fukuoka Y., Nakahara Y., Kawamoto Y., et al. Cutting edge: CD8+CD122+ regulatory T cells produce IL-10 to suppress IFN-gamma production and proliferation of CD8+ T cells. J Immunol 175 (2005) 7093-7097
65. Saitoh O., Abiru N., Nakahara M., and Nagayama Y. CD8+CD122+ T cells, a newly identified regulatory T subset, negatively regulate Graves' hyperthyroidism in a murine model. Endocrinology 148 (2007) 6040-6046
66. Zheng S.G., Wang J.H., Koss M.N., Quismorio Jr. F., Gray J.D., and Horwitz D.A. CD4+ and CD8+ regulatory T cells generated ex vivo with IL-2 and TGF-beta suppress a stimulatory graft-versus-host disease with a lupus-like syndrome. J Immunol 172 (2004) 1531-1539
67. Ho J., Kurtz C.C., Naganuma M., Ernst P.B., Cominelli F., and Rivera-Nieves J. A CD8+/CD103high T cell subset regulates TNF-mediated chronic murine ileitis. J Immunol 180 (2008) 2573-2580
68. Kang H.K., Michaels M.A., Berner B.R., and Datta S.K. Very low-dose tolerance with nucleosomal peptides controls lupus and induces potent regulatory T cell subsets. J Immunol 174 (2005) 3247-3255
69. Seo S.K., Choi J.H., Kim Y.H., Kang W.J., Park H.Y., Suh J.H., et al. 4-1BB-mediated immunotherapy of rheumatoid arthritis. Nat Med 10 (2004) 1088-1094
70. Klimiuk P.A., Goronzy J.J., and Weyand C.M. IL-16 as an anti-inflammatory cytokine in rheumatoid synovitis. J Immunol 162 (1999) 4293-4299
71. Chang C.C., Ciubotariu R., Manavalan J.S., Yuan J., Colovai A.I., Piazza F., et al. Tolerization of dendritic cells by T(S) cells: the crucial role of inhibitory receptors ILT3 and ILT4. Nat Immunol 3 (2002) 237-243
72. Manavalan J.S., Kim-Schulze S., Scotto L., Naiyer A.J., Vlad G., Colombo P.C., et al. Alloantigen specific CD8+CD28- FOXP3+ T suppressor cells induce ILT3+ ILT4+ tolerogenic endothelial cells, inhibiting alloreactivity. Int Immunol 16 (2004) 1055-1068
73. Suciu-Foca N., and Cortesini R. Central role of ILT3 in the T suppressor cell cascade. Cell Immunol 248 (2007) 59-67
74. Tiemessen M.M., Jagger A.L., Evans H.G., van Herwijnen M.J., John S., and Taams L.S. CD4+CD25+Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages. Proc Natl Acad Sci U S A 104 (2007) 19446-19451
75. Davila E., Kang Y.M., Park Y.W., Sawai H., He X., Pryshchep S., et al. Cell-based immunotherapy with suppressor CD8+ T cells in rheumatoid arthritis. J Immunol 174 (2005) 7292-7301
76. Shi Z., Rifa'i M., Lee Y.H., Shiku H., Isobe K., and Suzuki H. Importance of CD80/CD86-CD28 interactions in the recognition of target cells by CD8+CD122+ regulatory T cells. Immunology 124 (2008) 121-128
77. Jiang H., Ware R., Stall A., Flaherty L., Chess L., and Pernis B. Murine CD8+ T cells that specifically delete autologous CD4+ T cells expressing V beta 8 TCR: a role of the Qa-1 molecule. Immunity 2 (1995) 185-194
78. Sarantopoulos S., Lu L., and Cantor H. Qa-1 restriction of CD8+ suppressor T cells. J Clin Invest 114 (2004) 1218-1221
79. Tennakoon D.K., Mehta R.S., Ortega S.B., Bhoj V., Racke M.K., and Karandikar N.J. Therapeutic induction of regulatory, cytotoxic CD8+ T cells in multiple sclerosis. J Immunol 176 (2006) 7119-7129
80. Hu D., Ikizawa K., Lu L., Sanchirico M.E., Shinohara M.L., and Cantor H. Analysis of regulatory CD8 T cells in Qa-1-deficient mice. Nat Immunol 5 (2004) 516-523
81. Eilat E., Dayan M., Zinger H., and Mozes E. The mechanism by which a peptide based on complementarity-determining region-1 of a pathogenic anti-DNA auto-Ab ameliorates experimental systemic lupus erythematosus. Proc Natl Acad Sci U S A 98 (2001) 1148-1153
82. Sharabi A., Haviv A., Zinger H., Dayan M., and Mozes E. Amelioration of murine lupus by a peptide, based on the complementarity determining region-1 of an autoantibody as compared to dexamethasone: different effects on cytokines and apoptosis. Clin Immunol 119 (2006) 146-155
83. Hahn B.H., Singh R.R., Wong W.K., Tsao B.P., Bulpitt K., and Ebling F.M. Treatment with a consensus peptide based on amino acid sequences in autoantibodies prevents T cell activation by autoantigens and delays disease onset in murine lupus. Arthritis Rheum 44 (2001) 432-441
84. Ohnishi K., Ebling F.M., Mitchell B., Singh R.R., Hahn B.H., and Tsao B.P. Comparison of pathogenic and non-pathogenic murine antibodies to DNA: antigen binding and structural characteristics. Int Immunol 6 (1994) 817-830
85. Tsao B.P., Ebling F.M., Roman C., Panosian-Sahakian N., Calame K., and Hahn B.H. Structural characteristics of the variable regions of immunoglobulin genes encoding a pathogenic autoantibody in murine lupus. J Clin Invest 85 (1990) 530-540
86. Singh R.R., Ebling F.M., Albuquerque D.A., Saxena V., Kumar V., Giannini E.H., et al. Induction of autoantibody production is limited in nonautoimmune mice. J Immunol 169 (2002) 587-594
87. La Cava A., Ebling F.M., and Hahn B.H. Ig-reactive CD4+CD25+ T cells from tolerized (New Zealand Black x New Zealand White)F1 mice suppress in vitro production of antibodies to DNA. J Immunol 173 (2004) 3542-3548
88. Okazaki T., and Honjo T. The PD-1-PD-L pathway in immunological tolerance. Trends Immunol 27 (2006) 195-201
89. Keir M.E., Liang S.C., Guleria I., Latchman Y.E., Qipo A., Albacker L.A., et al. Tissue expression of PD-L1 mediates peripheral T cell tolerance. J Exp Med 203 (2006) 883-895
90. Keir M.E., Francisco L.M., and Sharpe A.H. PD-1 and its ligands in T-cell immunity. Curr Opin Immunol 19 (2007) 309-314
91. Sharpe A.H., Wherry E.J., Ahmed R., and Freeman G.J. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol 8 (2007) 239-245
92. Skaggs B.J., Singh R.P., and Hahn B.H. Induction of immune tolerance by activation of CD8+ T suppressor/regulatory cells in lupus-prone mice. Hum Immunol 69 (2008) 790-796
93. Barber D.L., Wherry E.J., Masopust D., Zhu B., Allison J.P., Sharpe A.H., et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439 (2006) 682-687
94. Golden-Mason L., Klarquist J., Wahed A.S., and Rosen H.R. Cutting edge: programmed death-1 expression is increased on immunocytes in chronic hepatitis C virus and predicts failure of response to antiviral therapy: race-dependent differences. J Immunol 180 (2008) 3637-3641
95. Peng G., Li S., Wu W., Tan X., Chen Y., and Chen Z. PD-1 upregulation is associated with HBV-specific T cell dysfunction in chronic hepatitis B patients. Mol Immunol 45 (2008) 963-970
96. Trautmann L., Janbazian L., Chomont N., Said E.A., Gimmig S., Bessette B., et al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat Med 12 (2006) 1198-1202
97. Day C.L., Kaufmann D.E., Kiepiela P., Brown J.A., Moodley E.S., Reddy S., et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443 (2006) 350-354
98. Penna A., Pilli M., Zerbini A., Orlandini A., Mezzadri S., Sacchelli L., et al. Dysfunction and functional restoration of HCV-specific CD8 responses in chronic hepatitis C virus infection. Hepatology 45 (2007) 588-601
99. Rutebemberwa A., Ray S.C., Astemborski J., Levine J., Liu L., Dowd K.A., et al. High-programmed death-1 levels on hepatitis C virus-specific T cells during acute infection are associated with viral persistence and require preservation of cognate antigen during chronic infection. J Immunol 181 (2008) 8215-8225
100. Boni C., Fisicaro P., Valdatta C., Amadei B., Di Vincenzo P., Giuberti T., et al. Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection. J Virol 81 (2007) 4215-4225
101. Sharabi A., Zinger H., Zborowsky M., Sthoeger Z.M., and Mozes E. A peptide based on the complementarity-determining region 1 of an autoantibody ameliorates lupus by up-regulating CD4+CD25+ cells and TGF-beta. Proc Natl Acad Sci U S A 103 (2006) 8810-8815
102. Sharabi A., Luger D., Ben-David H., Dayan M., Zinger H., and Mozes E. The role of apoptosis in the ameliorating effects of a CDR1-based peptide on lupus manifestations in a mouse model. J Immunol 179 (2007) 4979-4987
103. Sharabi A., Azulai H., Sthoeger Z.M., and Mozes E. Clinical amelioration of murine lupus by a peptide based on the complementarity determining region-1 of an autoantibody and by cyclophosphamide: similarities and differences in the mechanisms of action. Immunology 121 (2007) 248-257
104. Rapoport M.J., Sharabi A., Aharoni D., Bloch O., Zinger H., Dayan M., et al. Amelioration of SLE-like manifestations in (NZBxNZW)F1 mice following treatment with a peptide based on the complementarity determining region 1 of an autoantibody is associated with a down-regulation of apoptosis and of the pro-apoptotic factor JNK kinase. Clin Immunol 117 (2005) 262-270
105. Sharabi A., and Mozes E. The suppression of murine lupus by a tolerogenic peptide involves foxp3-expressing CD8 cells that are required for the optimal induction and function of foxp3-expressing CD4 cells. J Immunol 181 (2008) 3243-3251
106. Miyara M., Amoura Z., Parizot C., Badoual C., Dorgham K., Trad S., et al. Global natural regulatory T cell depletion in active systemic lupus erythematosus. J Immunol 175 (2005) 8392-8400
107. Gerli R., Nocentini G., Alunno A., Bocci E.B., Bianchini R., Bistoni O., et al. Identification of regulatory T cells in systemic lupus erythematosus. Autoimmun Rev 8 (2009) 426-430
108. Yates J., Whittington A., Mitchell P., Lechler R.I., Lightstone L., and Lombardi G. Natural regulatory T cells: number and function are normal in the majority of patients with lupus nephritis. Clin Exp Immunol 153 (2008) 44-55
109. Zhang B., Zhang X., Tang F.L., Zhu L.P., Liu Y., and Lipsky P.E. Clinical significance of increased CD4+CD25-Foxp3+ T cells in patients with new-onset systemic lupus erythematosus. Ann Rheum Dis 67 (2008) 1037-1040
110. Sthoeger Z.M., Sharabi A., Dayan M., Zinger H., Asher I., Sela U., et al. The tolerogenic peptide hCDR1 downregulates pathogenic cytokines and apoptosis and upregulates immunosuppressive molecules and regulatory T cells in peripheral blood mononuclear cells of lupus patients. Hum Immunol 70 (2009) 139-145
111. Hahn B.H., Anderson M., Le E., and La Cava A. Anti-DNA Ig peptides promote Treg cell activity in systemic lupus erythematosus patients. Arthritis Rheum 58 (2008) 2488-2497
112. Filaci G., Bacilieri S., Fravega M., Monetti M., Contini P., Ghio M., et al. Impairment of CD8+ T suppressor cell function in patients with active systemic lupus erythematosus. J Immunol 166 (2001) 6452-6457
113. Tulunay A., Yavuz S., Direskeneli H., and Eksioglu-Demiralp E. CD8+CD28-, suppressive T cells in systemic lupus erythematosus. Lupus 17 (2008) 630-637
114. Alvarado-Sanchez B., Hernandez-Castro B., Portales-Perez D., Baranda L., Layseca-Espinosa E., Abud-Mendoza C., et al. Regulatory T cells in patients with systemic lupus erythematosus. J Autoimmun 27 (2006) 110-118
115. Zhang L., Bertucci A.M., Ramsey-Goldman R., Burt R.K., and Datta S.K. Regulatory T cell (Treg) subsets return in patients with refractory lupus following stem cell transplantation, and TGF-beta-producing CD8+ Treg cells are associated with immunological remission of lupus. J Immunol 183 (2009) 6346-6358
116. Notley CA, McCann FE, Inglis JJ and Williams RO. ANTI-CD3 therapy expands the numbers of CD4+ and CD8+ treg cells and induces sustained amelioration of collagen-induced arthritis. Arthritis Rheum 2010;62:171-8.
117. Lassmann H. Experimental models of multiple sclerosis. Rev Neurol 163 (2007) 651-655 (Paris)
118. Lee Y.H., Ishida Y., Rifa'i M., Shi Z., Isobe K., and Suzuki H. Essential role of CD8+CD122+ regulatory T cells in the recovery from experimental autoimmune encephalomyelitis. J Immunol 180 (2008) 825-832
119. Zozulya A.L., Ortler S., Fabry Z., Sandor M., and Wiendl H. The level of B7 homologue 1 expression on brain DC is decisive for CD8 Treg cell recruitment into the CNS during EAE. Eur J Immunol 39 (2009) 1536-1543
120. Zozulya A.L., Ortler S., Lee J., Weidenfeller C., Sandor M., Wiendl H., et al. Intracerebral dendritic cells critically modulate encephalitogenic versus regulatory immune responses in the CNS. J Neurosci 29 (2009) 140-152
121. Chen M.L., Yan B.S., Kozoriz D., and Weiner H.L. Novel CD8(+) regulatory T cells suppress experimental autoimmune encephalomyelitis by TGF-beta- and IFN-gamma-dependent mechanisms. Eur J Immunol 34 (2009) 3423-3435
122. Ben-David H., Sharabi A., Dayan M., Sela M., and Mozes E. The role of CD8+CD28 regulatory cells in suppressing myasthenia gravis-associated responses by a dual altered peptide ligand. Proc Natl Acad Sci U S A 104 (2007) 17459-17464
123. Harrison L.C., Dempsey-Collier M., Kramer D.R., and Takahashi K. Aerosol insulin induces regulatory CD8 gamma delta T cells that prevent murine insulin-dependent diabetes. J Exp Med 184 (1996) 2167-2174
124. Wang R., Han G., Song L., Wang J., Chen G., Xu R., et al. CD8+ regulatory T cells are responsible for GAD-IgG gene-transferred tolerance induction in NOD mice. Immunology 126 (2009) 123-131
125. Li S., Gowans E.J., Chougnet C., Plebanski M., and Dittmer U. Natural regulatory T cells and persistent viral infection. J Virol 82 (2008) 21-30
126. Belkaid Y., and Rouse B.T. Natural regulatory T cells in infectious disease. Nat Immunol 6 (2005) 353-360
127. Belkaid Y. Regulatory T cells and infection: a dangerous necessity. Nat Rev Immunol 7 (2007) 875-888
128. Accapezzato D., Francavilla V., Paroli M., Casciaro M., Chircu L.V., Cividini A., et al. Hepatic expansion of a virus-specific regulatory CD8(+) T cell population in chronic hepatitis C virus infection. J Clin Invest 113 (2004) 963-972
129. Alatrakchi N., Graham C.S., van der Vliet H.J., Sherman K.E., Exley M.A., and Koziel M.J. Hepatitis C virus (HCV)-specific CD8+ cells produce transforming growth factor beta that can suppress HCV-specific T-cell responses. J Virol 81 (2007) 5882-5892
130. Elrefaei M., Barugahare B., Ssali F., Mugyenyi P., and Cao H. HIV-specific IL-10-positive CD8+ T cells are increased in advanced disease and are associated with decreased HIV-specific cytolysis. J Immunol 176 (2006) 1274-1280
131. Elrefaei M., Ventura F.L., Baker C.A., Clark R., Bangsberg D.R., and Cao H. HIV-specific IL-10-positive CD8+ T cells suppress cytolysis and IL-2 production by CD8+ T cells. J Immunol 178 (2007) 3265-3271
132. Elrefaei M., Baker C.A., Jones N.G., Bangsberg D.R., and Cao H. Presence of suppressor HIV-specific CD8+ T cells is associated with increased PD-1 expression on effector CD8+ T cells. J Immunol 180 (2008) 7757-7763
133. Kornfeld C., Ploquin M.J., Pandrea I., Faye A., Onanga R., Apetrei C., et al. Antiinflammatory profiles during primary SIV infection in African green monkeys are associated with protection against AIDS. J Clin Invest 115 (2005) 1082-1091
134. Karlsson I., Malleret B., Brochard P., Delache B., Calvo J., Le Grand R., et al. FoxP3+ CD25+ CD8+ T-cell induction during primary simian immunodeficiency virus infection in cynomolgus macaques correlates with low CD4+ T-cell activation and high viral load. J Virol 81 (2007) 13444-13455
135. Nordstrom I., Nurkkala M., Collins L.V., and Eriksson K. CD8+ T-cells suppress antigen-specific and allogeneic CD4+ T-cell responses to herpes simplex virus type 2-infected human dendritic cells. Viral Immunol 18 (2005) 616-626
136. Garba M.L., Pilcher C.D., Bingham A.L., Eron J., and Frelinger J.A. HIV antigens can induce TGF-beta(1)-producing immunoregulatory CD8+ T cells. J Immunol 168 (2002) 2247-2254
137. Brooks D.G., Trifilo M.J., Edelmann K.H., Teyton L., McGavern D.B., and Oldstone M.B. Interleukin-10 determines viral clearance or persistence in vivo. Nat Med 12 (2006) 1301-1309
138. Ejrnaes M., Filippi C.M., Martinic M.M., Ling E.M., Togher L.M., Crotty S., et al. Resolution of a chronic viral infection after interleukin-10 receptor blockade. J Exp Med 203 (2006) 2461-2472
139. Wang H.Y., Lee D.A., Peng G., Guo Z., Li Y., Kiniwa Y., et al. Tumor-specific human CD4+ regulatory T cells and their ligands: implications for immunotherapy. Immunity 20 (2004) 107-118
140. van der Burg S.H., Piersma S.J., de Jong A., van der Hulst J.M., Kwappenberg K.M., van den Hende M., et al. Association of cervical cancer with the presence of CD4+ regulatory T cells specific for human papillomavirus antigens. Proc Natl Acad Sci U S A 104 (2007) 12087-12092
141. Voo K.S., Peng G., Guo Z., Fu T., Li Y., Frappier L., et al. Functional characterization of EBV-encoded nuclear antigen 1-specific CD4+ helper and regulatory T cells elicited by in vitro peptide stimulation. Cancer Res 65 (2005) 1577-1586
142. Wang H.Y., Peng G., Guo Z., Shevach E.M., and Wang R.F. Recognition of a new ARTC1 peptide ligand uniquely expressed in tumor cells by antigen-specific CD4+ regulatory T cells. J Immunol 174 (2005) 2661-2670
143. Zou W. Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 6 (2006) 295-307
144. Wang R.F. CD8+ regulatory T cells, their suppressive mechanisms, and regulation in cancer. Hum Immunol 69 (2008) 811-814
145. Chaput N., Louafi S., Bardier A., Charlotte F., Vaillant J.C., Menegaux F., et al. Identification of CD8+CD25+Foxp3+ suppressive T cells in colorectal cancer tissue. Gut 58 (2009) 520-529
146. Meloni F., Morosini M., Solari N., Passadore I., Nascimbene C., Novo M., et al. Foxp3 expressing CD4+ CD25+ and CD8+CD28- T regulatory cells in the peripheral blood of patients with lung cancer and pleural mesothelioma. Hum Immunol 67 (2006) 1-12
147. Jarnicki A.G., Lysaght J., Todryk S., and Mills K.H. Suppression of antitumor immunity by IL-10 and TGF-beta-producing T cells infiltrating the growing tumor: influence of tumor environment on the induction of CD4+ and CD8+ regulatory T cells. J Immunol 177 (2006) 896-904
148. Vlad G., Cortesini R., and Suciu-Foca N. License to heal: bidirectional interaction of antigen-specific regulatory T cells and tolerogenic APC. J Immunol 174 (2005) 5907-5914
149. Zhang L., Jarvis L.B., Baek H.J., and Gaston J.S. Regulatory IL4+CD8+ T cells in patients with ankylosing spondylitis and healthy controls. Ann Rheum Dis 68 (2009) 1345-1351
150. Rifa'i M., Shi Z., Zhang S.Y., Lee Y.H., Shiku H., Isobe K., et al. CD8+CD122+ regulatory T cells recognize activated T cells via conventional MHC class I-alphabetaTCR interaction and become IL-10-producing active regulatory cells. Int Immunol 20 (2008) 937-947