The ubiquitin E3 ligase Cbl-b in T cells tolerance and tumor immunity

Cell Cycle

Volumn 6, Issue 20, 2007, Pages 2478-2485

  Loeser, Stefanie ^a   Penninger, Josef M ^a  

^a ERICH SCHMID INSTITUTE OF MATERIALS SCIENCE   (Austria)

Author keywords

Autoimmunity; Cbl b; t cell; Tolerance; Tumor immunity; Ubiquitination

Indexed keywords

CBL PROTEIN; TUMOR ANTIGEN; UBIQUITIN PROTEIN LIGASE E3; VASCULAR CELL ADHESION MOLECULE 1;

CANCER IMMUNOTHERAPY; CANCER INHIBITION; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL ACTIVATION; CELL PROLIFERATION; CYTOTOXIC LYMPHOCYTE; DENDRITIC CELL; ENZYME INHIBITION; IMMUNE SYSTEM; IMMUNOLOGICAL TOLERANCE; IMMUNOSUPPRESSIVE TREATMENT; IMMUNOSURVEILLANCE; MAJOR HISTOCOMPATIBILITY COMPLEX; MODULATION; NONHUMAN; REGULATORY T LYMPHOCYTE; REVIEW; T LYMPHOCYTE; T LYMPHOCYTE ACTIVATION; TUMOR IMMUNITY; TUMOR REJECTION; UBIQUITINATION;

MUS;

EID: 35848949545     PISSN: 15384101     EISSN: 15514005     Source Type: Journal    
DOI: 10.4161/cc.6.20.4797     Document Type: Review

References (130)

1. Ehrlich P. Ueber den jetzigen Stand der Karzinomforschung. Ned Tijdschr Geneeskd 1909; 5:273-90.
2. Pardoll DM. New strategies for enhancing the immunogenicity of tumors. Curr Opin Immunol 1993; 5:719-25.
3. Thomas L, ed. Discussion. In Cellular and Humoral Aspects of the Hypersensitive States, 1959.
4. Burnet FM. The concept of immunological surveillance. Prog Exp Tumor Res 1970; 13:1-27.
5. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: From immunosurveillance to tumor escape. Nat Immunol 2002; 3:991-8.
6. Janeway Jr CA. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol 1989; 54(Pt 1):1-13.
7. Sternlicht MD, Werb Z. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol 2001; 17:463-516.
8. Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol 1994; 12:991-1045.
9. Vicari AP, Caux C. Chemokines in cancer. Cytokine Growth Factor Rev 2002; 13:143-54.
10. Benlagha K, Bendelac A. CD1d-restricted mouse V alpha 14 and human V alpha 24 T cells: Lymphocytes of innate immunity. Semin Immunol 2000; 12:537-42.
11. Bromberg JF, Horvath CM, Wen Z, Schreiber RD, Darnell Jr JE. Transcriptionally active Stat1 is required for the antiproliferative effects of both interferon alpha and interferon gamma. Proc Natl Acad Sci USA 1996; 93:7673-8.
12. Kumar A, Commane M, Flickinger TW, Horvath CM, Stark GR. Defective TNF-alpha-induced apoptosis in STAT1-null cells due to low constitutive levels of caspases. Science 1997; 278:1630-2.
13. Luster AD, Leder P. IP-10, a -C-X-C- chemokine, elicits a potent thymus-dependent antitumor response in vivo. J Exp Med 1993; 178:1057-65.
14. Coughlin CM, Salhany KE, Gee MS, LaTemple DC, Kotenko S, Ma X, Gri G, Wysocka M, Kim JE, Liu L, Liao F, Farber JM, Pestka S, Trinchieri G, Lee WM. Tumor cell responses to IFNgamma affect tumorigenicity and response to IL-12 therapy and antiangiogenesis. Immunity 1998; 9:25-34.
15. Qin Z, Blankenstein T. CD4+ T cell-mediated tumor rejection involves inhibition of angiogenesis that is dependent on IFN gamma receptor expression by nonhematopoietic cells. Immunity 2000; 12:677-86.
16. Nathan CF, Murray HW, Wiebe ME, Rubin BY. Identification of interferon-gamma as the lymphokine that activates human macrophage oxidative metabolism and antimicrobial activity. J Exp Med 1983; 158:670-89.
17. Smyth MJ, Cretney E, Takeda K, Wiltrout RH, Sedger LM, Kayagaki N, Yagita H, Okumura K. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) contributes to interferon gamma-dependent natural killer cell protection from tumor metastasis. J Exp Med 2001; 193:661-70.
18. Takeda K, Smyth MJ, Cretney E, Hayakawa Y, Yamaguchi N, Yagita H, Okumura K. Involvement of tumor necrosis factor-related apoptosis-inducing ligand in NK cell-mediated and IFN-gamma-dependent suppression of subcutaneous tumor growth. Cell Immunol 2001; 214:194-200.
19. Hayakawa Y, Kelly JM, Westwood JA, Darcy PK, Diefenbach A, Raulet D, Smyth MJ. Cutting edge: Tumor rejection mediated by NKG2D receptor-ligand interaction is dependent upon perforin. J Immunol 2002; 169:5377-81.
20. Gerosa F, Baldani-Guerra B, Nisii C, Marchesini V, Carra G, Trinchieri G. Reciprocal activating interaction between natural killer cells and dendritic cells. J Exp Med 2002; 195:327-33.
21. Sallusto F, Mackay CR, Lanzavecchia A. The role of chemokine receptors in primary, effector, and memory immune responses. Annu Rev Immunol 2000; 18:593-620.
22. Schoenberger SP, Toes RE, van der Voort EI, Offringa R, Melief CJ. T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature 1998; 393:480-3.
23. Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol 2004; 22:329-60.
24. Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity 2004; 21:137-48.
25. Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting doi:10.1146/annurev.immunol.22.012703.104803. Annual Review of Immunology 2004; 22:329-60.
26. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, Lennon VA, Celis E, Chen L. Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion. Nat Med 2002; 8:793-800.
27. Gorelik L, Flavell RA. Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells. Nat Med 2001; 7:1118-22.
28. Chen ML, Pittet MJ, Gorelik L, Flavell RA, Weissleder R, von Boehmer H, Khazaie K. Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-beta signals in vivo. Proc Natl Acad Sci USA 2005; 102:419-24.
29. Zhang Q, Yang X, Pins M, Javonovic B, Kuzel T, Kim SJ, Parijs LV, Greenberg NM, Liu V, Guo Y, Lee C. Adoptive transfer of tumor-reactive transforming growth factor-beta-insensitive CD8+ T cells: Eradication of autologous mouse prostate cancer. Cancer Res 2005; 65:1761-9.
30. Gabrilovich DI, Ishida T, Nadaf S, Ohm JE, Carbone DP. Antibodies to vascular endothelial growth factor enhance the efficacy of cancer immunotherapy by improving endogenous dendritic cell function. Clin Cancer Res 1999; 5:2963-70.
31. Kawamura K, Bahar R, Natsume W, Sakiyama S, Tagawa M. Secretion of interleukin-10 from murine colon carcinoma cells suppresses systemic antitumor immunity and impairs protective immunity induced against the tumors. Cancer Gene Ther 2002; 9:109-15.
32. Munn DH, Mellor AL. Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J Clin Invest 2007; 117:1147-54.
33. Schwartz RH. T cell anergy. Annu Rev Immunol 2003; 21:305-34.
34. Marincola FM, Jaffee EM, Hicklin DJ, Ferrone S. Escape of human solid tumors from T-cell recognition: Molecular mechanisms and functional significance. Adv Immunol 2000; 74:181-273.
35. Wohlfart S, Sebinger D, Gruber P, Buch J, Polgar D, Krupitza G, Rosner M, Hengstschlager M, Raderer M, Chott A, Mullauer L. FAS (CD95) mutations are rare in gastric MALT lymphoma but occur more frequently in primary gastric diffuse large B-cell lymphoma. Am J Pathol 2004; 164:1081-9.
36. Kataoka T, Schroter M, Hahne M, Schneider P, Irmler M, Thome M, Froelich CJ, Tschopp J. FLIP prevents apoptosis induced by death receptors but not by perforin/granzyme B, chemotherapeutic drugs, and gamma irradiation. J Immunol 1998; 161:3936-42.
37. Hinz S, Trauzold A, Boenicke L, Sandberg C, Beckmann S, Bayer E, Walczak H, Kalthoff H, Ungefroren H. Bcl-XL protects pancreatic adenocarcinoma cells against CD95- and TRAIL-receptor-mediated apoptosis. Oncogene 2000; 19:5477-86.
38. June CH. Principles of adoptive T cell cancer therapy. J Clin Invest 2007; 117:1204-12.
39. Gattinoni L, Powell Jr DJ, Rosenberg SA, Restifo NP. Adoptive immunotherapy for cancer: Building on success. Nat Rev Immunol 2006; 6:383-93.
40. Swann JB, Smyth MJ. Immune surveillance of tumors. J Clin Invest 2007; 117:1137-46.
41. Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: Moving beyond current vaccines. Nat Med 2004; 10:909-15.
42. Melero I, Hervas?Stubbs S, Glennie M, Pardoll DM, Chen L. Immunostimulatory monoclonal antibodies for cancer therapy. Nat Rev Cancer 2007; 7:95-106.
43. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996; 271:1734-6.
44. Curiel TJ, Wei S, Dong H, Alvarez X, Cheng P, Mottram P, Krzysiek R, Knutson KL, Daniel B, Zimmermann MC, David O, Burow M, Gordon A, Dhurandhar N, Myers L, Berggren R, Hemminki A, Alvarez RD, Emilie D, Curiel DT, Chen L, Zou W. Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat Med 2003; 9:562-7.
45. Uyttenhove C, Pilotte L, Theate I, Stroobant V, Colau D, Parmentier N, Boon T, Van den Eynde BJ. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med 2003; 9:1269-74.
46. Munn DH, Sharma MD, Hou D, Baban B, Lee JR, Antonia SJ, Messina JL, Chandler P, Koni PA, Mellor AL. Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes. J Clin Invest 2004; 114:280-90.
47. Vonderheide RH, Dutcher JP, Anderson JE, Eckhardt SG, Stephans KF, Razvillas B, Garl S, Butine MD, Perry VP, Armitage RJ, Ghalie R, Caron DA, Gribben JG. Phase I study of recombinant human CD40 ligand in cancer patients. J Clin Oncol 2001; 19:3280-7.
48. Porter DL, Levine BL, Bunin N, Stadtmauer EA, Luger SM, Goldstein S, Loren A, Phillips J, Nasta S, Perl A, Schuster S, Tsai D, Sohal A, Veloso E, Emerson S, June CH. A phase 1 trial of donor lymphocyte infusions expanded and activated ex vivo via CD3/CD28 costimulation. Blood 2006; 107:1325-31.
49. Rapoport AP, Stadtmauer EA, Aqui N, Badros A, Cotte J, Chrisley L, Veloso E, Zheng Z, Westphal S, Mair R, Chi N, Ratterree B, Pochran MF, Natt S, Hinkle J, Sickles C, Sohal A, Ruehle K, Lynch C, Zhang L, Porter DL, Luger S, Guo C, Fang HB, Blackwelder W, Hankey K, Mann D, Edelman R, Frasch C, Levine BL, Cross A, June CH. Restoration of immunity in lymphopenic individuals with cancer by vaccination and adoptive T-cell transfer. Nat Med 2005; 11:1230-7.
50. 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; 61:8643-6.
51. Sutmuller RP, van Duivenvoorde LM, van Elsas A, Schumacher TN, Wildenberg ME, Allison JP, Toes RE, Offringa R, Melief CJ. 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; 194:823-32.
52. Dudley ME, Wunderlich JR, Robbins PF, Yang JC, Hwu P, Schwartzentruber DJ, Topalian SL, Sherry R, Restifo NP, Hubicki AM, Robinson MR, Raffeld M, Duray P, Seipp CA, Rogers-Freezer L, Morton KE, Mavroukakis SA, White DE, Rosenberg SA. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 2002; 298:850-4.
53. Attia P, Phan GQ, Maker AV, Robinson MR, Quezado MM, Yang JC, Sherry RM, Topalian SL, Kammula US, Royal RE, Restifo NP, Haworth LR, Levy C, Mavroukakis SA, Nichol G, Yellin MJ, Rosenberg SA. Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol 2005; 23:6043-53.
54. Maker AV, Phan GQ, Attia P, Yang JC, Sherry RM, Topalian SL, Kammula US, Royal RE, Haworth LR, Levy C, Kleiner D, Mavroukakis SA, Yellin M, Rosenberg SA. Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: A phase I/II study. Ann Surg Oncol 2005; 12:1005-16.
55. Beck KE, Blansfield JA, Tran KQ, Feldman AL, Hughes MS, Royal RE, Kammula US, Topalian SL, Sherry RM, Kleiner D, Quezado M, Lowy I, Yellin M, Rosenberg SA, Yang JC. Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. J Clin Oncol 2006; 24:2283-9.
56. Goodnow CC, Sprent J, Fazekas de St Groth B, Vinuesa CG. Cellular and genetic mechanisms of self tolerance and autoimmunity. Nature 2005; 435:590-7.
57. Venanzi ES, Benoist C, Mathis D. Good riddance: Thymocyte clonal deletion prevents autoimmunity. Curr Opin Immunol 2004; 16:197-202.
58. Mathis D, Benoist C. Back to central tolerance. Immunity 2004; 20:509-16.
59. Kyewski B, Derbinski J. Self-representation in the thymus: An extended view. Nat Rev Immunol 2004; 4:688-98.
60. Filion MC, Bradley AJ, Devine DV, Decary F, Chartrand P. Autoreactive T cells in healthy individuals show tolerance in vitro with characteristics similar to but distinct from clonal anergy. Eur J Immunol 1995; 25:3123-7.
61. Fontenot JD, Rudensky AY. A well adapted regulatory contrivance: Regulatory T cell development and the forkhead family transcription factor Foxp3. Nat Immunol 2005; 6:331-7.
62. Sakaguchi S, Ono M, Setoguchi R, Yagi H, Hori S, Fehervari Z, Shimizu J, Takahashi T, Nomura T. Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev 2006; 212:8-27.
63. Borde M, Barrington RA, Heissmeyer V, Carroll MC, Rao A. Transcriptional basis of lymphocyte tolerance. Immunol Rev 2006; 210:105-19.
64. Appleman LJ, Boussiotis VA. T cell anergy and costimulation. Immunol Rev 2003; 192:161-80.
65. Harding FA, McArthur JG, Gross JA, Raulet DH, Allison JP. CD28-mediated signalling costimulates murine T cells and prevents induction of anergy in T-cell clones. Nature 1992; 356:607-9.
66. Jenkins MK, Taylor PS, Norton SD, Urdahl KB. CD28 delivers a costimulatory signal involved in antigen-specific IL-2 production by human T cells. J Immunol 1991; 147:2461-6.
67. Lechler R, Chai JG, Marelli-Berg F, Lombardi G. The contributions of T-cell anergy to peripheral T-cell tolerance. Immunology 2001; 103:262-9.
68. Appleman LJ, Tzachanis D, Grader-Beck T, van Puijenbroek AA, Boussiotis VA. Helper T cell anergy: From biochemistry to cancer pathophysiology and therapeutics. J Mol Med 2001; 78:673-83.
69. Mirshahidi S, Huang CT, Sadegh-Nasseri S. Anergy in peripheral memory CD4(+) T cells induced by low avidity engagement of T cell receptor. J Exp Med 2001; 194:719-31.
70. Jenkins MK, Schwartz RH. Antigen presentation by chemically modified splenocytes induces antigen-specific T cell unresponsiveness in vitro and in vivo. J Exp Med 1987; 165:302-19.
71. Schwartz RH, Mueller DL, Jenkins MK, Quill H. T-cell clonal anergy. Cold Spring Harb Symp Quant Biol 1989; 54(Pt 2):605-10.
72. Salomon B, Bluestone JA. Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation. Annu Rev Immunol 2001; 19:225-52.
73. Heissmeyer V, Macian F, Im SH, Varma R, Feske S, Venuprasad K, Gu H, Liu YC, Dustin ML, Rao A. Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins. Nat Immunol 2004; 5:255-65.
74. Jeon MS, Atfield A, Venuprasad K, Krawczyk C, Sarao R, Elly C, Yang C, Arya S, Bachmaier K, Su L, Bouchard D, Jones R, Gronski M, Ohashi P, Wada T, Bloom D, Fathman CG, Liu YC, Penninger JM. Essential role of the E3 ubiquitin ligase Cbl-b in T cell anergy induction. Immunity 2004; 21:167-77.
75. Bachmaier K, Krawczyk C, Kozieradzki I, Kong YY, Sasaki T, Oliveira-dos-Santos A, Mariathasan S, Bouchard D, Wakeham A, Itie A, Le J, Ohashi PS, Sarosi I, Nishina H, Lipkowitz S, Penninger JM. Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b. Nature 2000; 403:211-6.
76. Chiang YJ, Kole HK, Brown K, Naramura M, Fukuhara S, Hu RJ, Jang IK, Gutkind JS, Shevach E, Gu H. Cbl-b regulates the CD28 dependence of T-cell activation. Nature 2000; 403:216-20.
77. Krawczyk CM, Jones RG, Atfield A, Bachmaier K, Arya S, Odermatt B, Ohashi PS, Penninger JM. Differential control of CD28-regulated in vivo immunity by the E3 ligase Cbl-b. J Immunol 2005; 174:1472-8.
78. Krawczyk C, Bachmaier K, Sasaki T, Jones RG, Snapper SB, Bouchard D, Kozieradzki I, Ohashi PS, Alt FW, Penninger JM. Cbl-b is a negative regulator of receptor clustering and raft aggregation in T cells. Immunity 2000; 13:463-73.
79. Weissman AM. Themes and variations on ubiquitylation. Nat Rev Mol Cell Biol 2001; 2:169-78.
80. Haglund K, Sigismund S, Polo S, Szymkiewicz I, Di Fiore PP, Dikic I. Multiple monoubiquitination of RTKs is sufficient for their endocytosis and degradation. Nat Cell Biol 2003; 5:461-6.
81. Liu YC. Ubiquitin ligases and the immune response. Annu Rev Immunol 2004; 22:81-127.
82. Soares L, Seroogy C, Skrenta H, Anandasabapathy N, Lovelace P, Chung CD, Engleman E, Fathman CG. Two isoforms of otubain 1 regulate T cell anergy via GRAIL. Nat Immunol 2004; 5:45-54.
83. Anandasabapathy N, Ford GS, Bloom D, Holness C, Paragas V, Seroogy C, Skrenta H, Hollenhorst M, Fathman CG, Soares L. GRAIL: An E3 ubiquitin ligase that inhibits cytokine gene transcription is expressed in anergic CD4+ T cells. Immunity 2003; 18:535-47.
84. Fang D, Elly C, Gao B, Fang N, Altman Y, Joazeiro C, Hunter T, Copeland N, Jenkins N, Liu YC. Dysregulation of T lymphocyte function in itchy mice: A role for Itch in TH2 differentiation. Nat Immunol 2002; 3:281-7.
85. Seroogy CM, Soares L, Ranheim EA, Su L, Holness C, Bloom D, Fathman CG. The gene related to anergy in lymphocytes, an E3 ubiquitin ligase, is necessary for anergy induction in CD4 T cells. J Immunol 2004; 173:79-85.
86. Perry WL, Hustad CM, Swing DA, O'Sullivan TN, Jenkins NA, Copeland NG. The itchy locus encodes a novel ubiquitin protein ligase that is disrupted in a18H mice. Nat Genet 1998; 18:143-6.
87. Chang X, Chen L, Wen J, Godfrey VL, Qiao G, Hussien Y, Zhang J, Gao JX. Foxp3 controls autoreactive T cell activation through transcriptional regulation of early growth response genes and E3 ubiquitin ligase genes, independently of thymic selection. Clin Immunol 2006; 121:274-85.
88. Wohlfert EA, Callahan MK, Clark RB. Resistance to CD4+CD25+ regulatory T cells and TGF-beta in Cbl-b-/- mice. J Immunol 2004; 173:1059-65.
89. Safford M, Collins S, Lutz MA, Allen A, Huang CT, Kowalski J, Blackford A, Horton MR, Drake C, Schwartz RH, Powell JD. Egr-2 and Egr-3 are negative regulators of T cell activation. Nat Immunol 2005; 6:472-80.
90. Macian F. NFAT proteins: Key regulators of T-cell development and function. Nat Rev Immunol 2005; 5:472-84.
91. Macian F, Garcia-Cozar F, Im SH, Horton HF, Byrne MC, Rao A. Transcriptional mechanisms underlying lymphocyte tolerance. Cell 2002; 109:719-31.
92. Zhang J, Bardos T, Li D, Gal I, Vermes C, Xu J, Mikecz K, Finnegan A, Lipkowitz S, Glant TT. Cutting edge: Regulation of T cell activation threshold by CD28 costimulation through targeting Cbl-b for ubiquitination. J Immunol 2002; 169:2236-40.
93. Magnifico A, Ettenberg S, Yang C, Mariano J, Tiwari S, Fang S, Lipkowitz S, Weissman AM. WW domain HECT E3s target Cbl RING finger E3s for proteasomal degradation. J Biol Chem 2003; 278:43169-77.
94. Langdon WY, Hartley JW, Klinken SP, Ruscetti SK, Morse IIIrd HC. v-cbl, an oncogene from a dual-recombinant murine retrovirus that induces early B-lineage lymphomas. Proc Natl Acad Sci USA 1989; 86:1168-72.
95. Blake TJ, Shapiro M, Morse IIIrd HC, Langdon WY. The sequences of the human and mouse c-cbl proto-oncogenes show v-cbl was generated by a large truncation encompassing a proline-rich domain and a leucine zipper-like motif. Oncogene 1991; 6:653-7.
96. Keane MM, Ettenberg SA, Nau MM, Banerjee P, Cuello M, Penninger J, Lipkowitz S. cbl-3: A new mammalian cbl family protein. Oncogene 1999; 18:3365-75.
97. Keane MM, Rivero?Lezcano OM, Mitchell JA, Robbins KC, Lipkowitz S. Cloning and characterization of cbl-b: A SH3 binding protein with homology to the c-cbl proto-oncogene. Oncogene 1995; 10:2367-77.
98. Kim M, Tezuka T, Suziki Y, Sugano S, Hirai M, Yamamoto T. Molecular cloning and characterization of a novel cbl-family gene, cbl-c. Gene 1999; 239:145-54.
99. Huang F, Kitaura Y, Jang I, Naramura M, Kole HH, Liu L, Qin H, Schlissel MS, Gu H. Establishment of the major compatibility complex-dependent development of CD4+ and CD8+ T cells by the Cbl family proteins. Immunity 2006; 25:571-81.
100. Murphy MA, Schnall RG, Venter DJ, Barnett L, Bertoncello I, Thien CB, Langdon WY, Bowtell DD. Tissue hyperplasia and enhanced T-cell signalling via ZAP-70 in c-Cbl-deficient mice. Mol Cell Biol 1998; 18:4872-82.
101. Griffiths EK, Sanchez O, Mill P, Krawczyk C, Hojilla CV, Rubin E, Nau MM, Khokha R, Lipkowitz S, Hui CC, Penninger JM. Cbl-3-deficient mice exhibit normal epithelial development. Mol Cell Biol 2003; 23:7708-18.
102. Naramura M, Jang IK, Kole H, Huang F, Haines D, Gu H. c-Cbl and Cbl-b regulate T cell responsiveness by promoting ligand-induced TCR down-modulation. Nat Immunol 2002; 3:1192-9.
103. Gronski MA, Boulter JM, Moskophidis D, Nguyen LT, Holmberg K, Elford AR, Deenick EK, Kim HO, Penninger JM, Odermatt B, Gallimore A, Gascoigne NR, Ohashi PS. TCR affinity and negative regulation limit autoimmunity. Nat Med 2004; 10:1234-9.
104. Bachmaier K, Toya S, Gao X, Triantafillou T, Garrean S, Park GY, Frey RS, Vogel S, Minshall R, Christman JW, Tiruppathi C, Malik AB. E3 ubiquitin ligase Cblb regulates the acute inflammatory response underlying lung injury. Nat Med 2007.
105. Wohlfert EA, Gorelik L, Mittler R, Flavell RA, Clark RB. Cutting edge: Deficiency in the E3 ubiquitin ligase Cbl-b results in a multifunctional defect in T cell TGF-beta sensitivity in vitro and in vivo. J Immunol 2006; 176:1316-20.
106. zur Hausen H. Papillomavirus infections-a major cause of human cancers. Biochim Biophys Acta 1996; 1288:F55-78.
107. Pfeifer GP, You YH, Besaratinia A. Mutations induced by ultraviolet light. Mutat Res 2005; 571:19-31.
108. Bowden GT. Prevention of non-melanoma skin cancer by targeting ultraviolet-B-light signalling. Nat Rev Cancer 2004; 4:23-35.
109. Shreedhar VK, Pride MW, Sun Y, Kripke ML, Strickland FM. Origin and characteristics of ultraviolet-B radiation-induced suppressor T lymphocytes. J Immunol 1998; 161:1327-35.
110. Schwarz A, Beissert S, Grosse-Heitmeyer K, Gunzer M, Bluestone JA, Grabbe S, Schwarz T. Evidence for functional relevance of CTLA-4 in ultraviolet-radiation-induced tolerance. J Immunol 2000; 165:1824-31.
111. Loser K, Scherer A, Krummen MB, Varga G, Higuchi T, Schwarz T, Sharpe AH, Grabbe S, Bluestone JA, Beissert S. An important role of CD80/CD86-CTLA-4 signaling during photocarcinogenesis in mice. J Immunol 2005; 174:5298-305.
112. Loser K, Apelt J, Voskort M, Mohaupt M, Balkow S, Schwarz T, Grabbe S, Beissert S. IL-10 controls ultraviolet-induced carcinogenesis in mice. J Immunol 2007; 179:365-71.
113. Schwarz A, Maeda A, Wild MK, Kernebeck K, Gross N, Aragane Y, Beissert S, Vestweber D, Schwarz T. Ultraviolet radiation-induced regulatory T cells not only inhibit the induction but can suppress the effector phase of contact hypersensitivity. J Immunol 2004; 172:1036-43.
114. Grabbe S, Bruvers S, Lindgren AM, Hosoi J, Tan KC, Granstein RD. Tumor antigen presentation by epidermal antigen-presenting cells in the mouse: Modulation by granulocyte-macrophage colony-stimulating factor, tumor necrosis factor alpha, and ultraviolet radiation. J Leukoc Biol 1992; 52:209-17.
115. Beissert S, Ullrich SE, Hosoi J, Granstein RD. Supernatants from UVB radiation-exposed keratinocytes inhibit Langerhans cell presentation of tumor-associated antigens via IL-10 content. J Leukoc Biol 1995; 58:234-40.
116. Loeser S, Loser K, Bijker MS, Rangachari M, van der Burg SH, Wada T, Beissert S, Melief CJ, Penninger JM. Spontaneous tumor rejection by cbl-b-deficient CD8+ T cells. J Exp Med 2007; 204:879-91.
117. Willimsky G, Blankenstein T. Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance. Nature 2005; 437:141-6.
118. Zhang W, Shao Y, Fang D, Huang J, Jeon MS, Liu YC. Negative regulation of T cell antigen receptor-mediated Crk-L-C3G signaling and cell adhesion by Cbl-b. J Biol Chem 2003; 278:23978-83.
119. Mor A, Campi G, Du G, Zheng Y, Foster DA, Dustin ML, Philips MR. The lymphocyte function-associated antigen-1 receptor costimulates plasma membrane Ras via phospholipase D2. Nat Cell Biol 2007; 9:713-9.
120. Chiang JY, Jang IK, Hodes R, Gu H. Ablation of Cbl-b provides protection against transplanted and spontaneous tumors. J Clin Invest 2007; 117:1029-36.
121. Egawa T, Albrecht B, Favier B, Sunshine MJ, Mirchandani K, O'Brien W, Thome M, Littman DR. Requirement for CARMA1 in antigen receptor-induced NF-kappa B activation and lymphocyte proliferation. Curr Biol 2003; 13:1252-8.
122. Terabe M, Berzofsky JA. Immunoregulatory T cells in tumor immunity. Curr Opin Immunol 2004; 16:157-62.
123. Pages F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R, Mlecnik B, Kirilovsky A, Nilsson M, Damotte D, Meatchi T, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Galon J. Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 2005; 353:2654-66.
124. Williams MA, Bevan MJ. Effector and memory CTL differentiation. Annu Rev Immunol 2007; 25:171-92.
125. Sun JC, Williams MA, Bevan MJ. CD4+ T cells are required for the maintenance, not programming, of memory CD8+ T cells after acute infection. Nat Immunol 2004; 5:927-33.
126. Janssen EM, Lemmens EE, Wolfe T, Christen U, von Herrath MG, Schoenberger SP. CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature 2003; 421:852-6.
127. Lin KY, Lu D, Hung CF, Peng S, Huang L, Jie C, Murillo F, Rowley J, Tsai YC, He L, Kim DJ, Jaffee E, Pardoll D, Wu TC. Ectopic expression of vascular cell adhesion molecule-1 as a new mechanism for tumor immune evasion. Cancer Res 2007; 67:1832-41.
128. Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP, Thompson CB, Griesser H, Mak TW. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 1995; 270:985-8.
129. Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 1995; 3:541-7.
130. Phan GQ, Yang JC, Sherry RM, Hwu P, Topalian SL, Schwartzentruber DJ, Restifo NP, Haworth LR, Seipp CA, Freezer LJ, Morton KE, Mavroukakis SA, Duray PH, Steinberg SM, Allison JP, Davis TA, Rosenberg SA. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci USA 2003; 100:8372-7.