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Science 10 November 1995:
Vol. 270. no. 5238, pp. 985 - 988
DOI: 10.1126/science.270.5238.985
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Reports

Lymphoproliferative Disorders with Early Lethality in Mice Deficient in Ctla-4

Paul Waterhouse,  Josef M. Penninger,  Emma Timms,  Andrew Wakeham,  Arda Shahinian,  Kelvin P. Lee,  Craig B. Thompson,  Henrik Griesser,  Tak W. Mak (1)

The role of the cell-surface molecule CTLA-4 in the regulation of T cell activation has been controversial. Here, lymph nodes and spleens of CTLA-4-deficient mice accumulated T cell blasts with up-regulated activation markers. These blast cells also infiltrated liver, heart, lung, and pancreas tissue, and amounts of serum immunoglobulin were elevated. The mice invariably became moribund by 3 to 4 weeks of age. Although CTLA-4-deficient T cells proliferated spontaneously and strongly when stimulated through the T cell receptor, they were sensitive to cell death induced by cross-linking of the Fas receptor and by gamma irradiation. Thus, CTLA-4 acts as a negative regulator of T cell activation and is vital for the control of lymphocyte homeostasis.


P. Waterhouse, J. M. Penninger, E. Timms, A. Wakeham, A. Shahinian, T. W. Mak, Amgen Institute, Ontario Cancer Institute, Departments of Immunology and Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2C1, Canada.
K. P. Lee and C. B. Thompson, Howard Hughes Medical Institute, Gwen Knapp Center, University of Chicago, Chicago, IL , 60637, USA.
H. Griesser, Department of Pathology, University of Toronto, Toronto, Ontario M5G 2C1, Canada.
(1) To whom correspondence should be addressed.


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H. Ikegami, T. Awata, E. Kawasaki, T. Kobayashi, T. Maruyama, K. Nakanishi, A. Shimada, S. Amemiya, Y. Kawabata, S. Kurihara, et al. (2006)
J. Clin. Endocrinol. Metab. 91, 1087-1092
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Prolonged TCR/CD28 Engagement Drives IL-2-Independent T Cell Clonal Expansion through Signaling Mediated by the Mammalian Target of Rapamycin..
S. Colombetti, V. Basso, D. L. Mueller, and A. Mondino (2006)
J. Immunol. 176, 2730-2738
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Inhibition of the transcription factor foxp3 converts desmoglein 3-specific type 1 regulatory T cells into th2-like cells..
C. Veldman, A. Pahl, S. Beissert, W. Hansen, J. Buer, D. Dieckmann, G. Schuler, and M. Hertl (2006)
J. Immunol. 176, 3215-3222
   Abstract »    Full Text »    PDF »
Low Surface Expression of B7-1 (CD80) Is an Immunoescape Mechanism of Colon Carcinoma.
I. Tirapu, E. Huarte, C. Guiducci, A. Arina, M. Zaratiegui, O. Murillo, A. Gonzalez, C. Berasain, P. Berraondo, P. Fortes, et al. (2006)
Cancer Res. 66, 2442-2450
   Abstract »    Full Text »    PDF »
Antigen Exposure during Enhanced CTLA-4 Expression Promotes Allograft Tolerance In Vivo.
P. R. O. Salvalaggio, G. Camirand, C. E. Ariyan, S. Deng, L. Rogozinski, G. P. Basadonna, and D. M. Rothstein (2006)
J. Immunol. 176, 2292-2298
   Abstract »    Full Text »    PDF »
Defective Induction of CTLA-4 in the NOD Mouse Is Controlled by the NOD Allele of Idd3/IL-2 and a Novel Locus (Ctex) Telomeric on Chromosome 1.
M. Lundholm, V. Motta, A. Lofgren-Burstrom, N. Duarte, M.-L. Bergman, S. Mayans, and D. Holmberg (2006)
Diabetes 55, 538-544
   Abstract »    Full Text »    PDF »
Suppressor of cytokine signalling 1 in lymphocytes regulates the development of intestinal inflammation in mice.
K Inagaki-Ohara, A Sasaki, G Matsuzaki, T Ikeda, M Hotokezaka, K Chijiiwa, M Kubo, H Yoshida, Y Nawa, and A Yoshimura (2006)
Gut 55, 212-219
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Lack of Intrinsic CTLA-4 Expression Has Minimal Effect on Regulation of Antiviral T-Cell Immunity.
D. Homann, W. Dummer, T. Wolfe, E. Rodrigo, A. N. Theofilopoulos, M. B. A. Oldstone, and M. G. von Herrath (2006)
J. Virol. 80, 270-280
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Deficiency in Expression of the Signaling Protein Sin/Efs Leads to T-Lymphocyte Activation and Mucosal Inflammation.
L. T. Donlin, N. M. Danzl, C. Wanjalla, and K. Alexandropoulos (2005)
Mol. Cell. Biol. 25, 11035-11046
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CD80 Cytoplasmic Domain Controls Localization of CD28, CTLA-4, and Protein Kinase C{theta} in the Immunological Synapse.
S.-Y. Tseng, M. Liu, and M. L. Dustin (2005)
J. Immunol. 175, 7829-7836
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CTLA-4 Blockade: Autoimmunity As Treatment.
D. Kapadia and L. Fong (2005)
J. Clin. Oncol. 23, 8926-8928
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Antitumor Activity in Melanoma and Anti-Self Responses in a Phase I Trial With the Anti-Cytotoxic T Lymphocyte-Associated Antigen 4 Monoclonal Antibody CP-675,206.
A. Ribas, L. H. Camacho, G. Lopez-Berestein, D. Pavlov, C. A. Bulanhagui, R. Millham, B. Comin-Anduix, J. M. Reuben, E. Seja, C. A. Parker, et al. (2005)
J. Clin. Oncol. 23, 8968-8977
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On the Edge of Autoimmunity: T-Cell Stimulation by Steady-State Dendritic Cells Prevents Autoimmune Diabetes.
D. Bruder, A. M. Westendorf, W. Hansen, S. Prettin, A. D. Gruber, Y. Qian, H. von Boehmer, K. Mahnke, and J. Buer (2005)
Diabetes 54, 3395-3401
   Abstract »    Full Text »    PDF »
Analysis of the Cellular Mechanism of Antitumor Responses and Autoimmunity in Patients Treated with CTLA-4 Blockade.
A. V. Maker, P. Attia, and S. A. Rosenberg (2005)
J. Immunol. 175, 7746-7754
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Blockade of CTLA-4 (CD152) enhances the murine antibody response to pneumococcal capsular polysaccharides.
M. Boudewijns, A. Jeurissen, M. Wuyts, L. Moens, L. Boon, J. J. Van Neerven, A. Kasran, L. Overbergh, C. Lenaerts, M. Waer, et al. (2005)
J. Leukoc. Biol. 78, 1060-1069
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Regulation of B7.1 Costimulatory Molecule Is Mediated by the IFN Regulatory Factor-7 through the Activation of JNK in Lipopolysaccharide-Stimulated Human Monocytic Cells.
W. Lim, K. Gee, S. Mishra, and A. Kumar (2005)
J. Immunol. 175, 5690-5700
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Differential Effects of B and T Lymphocyte Attenuator and Programmed Death-1 on Acceptance of Partially versus Fully MHC-Mismatched Cardiac Allografts.
R. Tao, L. Wang, R. Han, T. Wang, Q. Ye, T. Honjo, T. L. Murphy, K. M. Murphy, and W. W. Hancock (2005)
J. Immunol. 175, 5774-5782
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Human CTLA4 knock-in mice unravel the quantitative link between tumor immunity and autoimmunity induced by anti-CTLA-4 antibodies.
K. D. Lute, K. F. May Jr, P. Lu, H. Zhang, E. Kocak, B. Mosinger, C. Wolford, G. Phillips, M. A. Caligiuri, P. Zheng, et al. (2005)
Blood 106, 3127-3133
   Abstract »    Full Text »    PDF »
Different cell surface oligomeric states of B7-1 and B7-2: Implications for signaling.
S. Bhatia, M. Edidin, S. C. Almo, and S. G. Nathenson (2005)
PNAS 102, 15569-15574
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