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http://dx.doi.org/10.4196/kjpp.2012.16.5.349

CTLA-4-Tg/CD-28-KO Mice Exhibit Reduced T Cell Proliferation in vivo Compared to CD-28-KO Mice in a Graft-versus-host Disease Model  

Yoo, Jong-Sun (Laboratory of Host Defense Modulation, College of Pharmacy, Chung-Ang University)
Lee, Yun-Jung (Laboratory of Host Defense Modulation, College of Pharmacy, Chung-Ang University)
Yoon, Joo-Won (Laboratory of Host Defense Modulation, College of Pharmacy, Chung-Ang University)
Hyung, Kyeong-Eun (Laboratory of Host Defense Modulation, College of Pharmacy, Chung-Ang University)
Hwang, Kwang-Woo (Laboratory of Host Defense Modulation, College of Pharmacy, Chung-Ang University)
Publication Information
The Korean Journal of Physiology and Pharmacology / v.16, no.5, 2012 , pp. 349-353 More about this Journal
Abstract
Activated T cells express inhibitory receptors such as CTLA-4 that can downregulate immune responses. Blockade of or genetic deficiency in CTLA-4 can result in autoimmunity. Therefore, strategies to increase the inhibitory function of CTLA-4 may be attractive in settings of undesirable T cell responses such as autoimmunity or transplant rejection. We have tested the hypothesis that transgenic constitutive expression of CTLA-4 can further attenuate immune responses when compared with normal inducible expression. Our results indicate that transgenic expression of CTLA-4 in mouse T cells (CTLA-4-Tg T cells) results in reduced cell cycle progression and increased apoptosis of TCR-stimulated T cells. CTLA-4-Tg T cells display reduced T cell proliferation in an in vivo model of graft versus host disease (GVHD). These results further our understanding of how CTLA-4 can be manipulated to inhibit immune responses and may help development of new therapeutic strategies for clinical settings of autoimmunity and transplantation.
Keywords
Cell surface molecules; Cellular activation; T lymphocytes; Transgenic; Rodent;
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1 Rao S, Vasu C, Martinez O, Kaithamana S, Prabhakar BS, Holterman MJ. Targeted delivery of anti-CTLA-4 antibody downregulates T cell function in vitro and in vivo. Clin Immunol. 2001;101:136-145.   DOI   ScienceOn
2 Vasu C, Gorla SR, Prabhakar BS, Holterman MJ. Targeted engagement of CTLA-4 prevents autoimmune thyroiditis. Int Immunol. 2003;15:641-654.   DOI   ScienceOn
3 Prud'homme GJ, Chang Y, Li X. Immunoinhibitory DNA vaccine protects against autoimmune diabetes through cDNA encoding a selective CTLA-4 (CD152) ligand. Hum Gene Ther. 2002;13395-13406.
4 Fecteau S, Basadonna GP, Freitas A, Ariyan C, Sayegh MH, Rothstein DM. CTLA-4 up-regulation plays a role in tolerance mediatedby CD45. Nat Immunol. 2001;2:58-63.   DOI   ScienceOn
5 Brunner MC, Chambers CA, Chan FK, Hanke J, Winoto A, Allison JP. CTLA-4-Mediated inhibition of early events of T cell proliferation. J Immunol. 1999;162:5813-5820.
6 Gribben JG, Freeman GJ, Boussiotis VA, Rennert P, Jellis CL, Greenfield E, Barber M, Restivo VA Jr, Ke X, Gray GS, et al. CTLA4 mediates antigen-specific apoptosis of human T cells. Proc Natl Acad Sci USA. 1995;92:811-815.   DOI   ScienceOn
7 Scheipers P, Reiser H. Fas-independent death of activated CD4(+) T lymphocytes induced by CTLA-4 crosslinking. Proc Natl Acad Sci USA. 1998;95:10083-10088.   DOI   ScienceOn
8 da Rocha Dias S, Rudd CE. CTLA-4 blockade of antigen-induced cell death. Blood. 2001;97:1134-1137.   DOI   ScienceOn
9 Lenschow DJ, Walunas TL, Bluestone JA. CD28/B7 system of T cell costimulation. Annu Rev Immunol. 1996;14:233-258.   DOI   ScienceOn
10 Blair PJ, Riley JL, Levine BL, Lee KP, Craighead N, Francomano T, Perfetto SJ, Gray GS, Carreno BM, June CH. CTLA-4 ligation delivers a unique signal to resting human CD4 T cells that inhibits interleukin-2 secretion but allows Bcl-X(L) induction. J Immunol. 1998;160:12-15.
11 Fallarino F, Fields PE, Gajewski TF. B7-1 engagement of cytotoxic T lymphocyte antigen 4 inhibits T cell activation in the absence of CD28. J Exp Med. 1998;188:205-210.   DOI   ScienceOn
12 Engelhardt JJ, Sullivan TJ, Allison JP. CTLA-4 overexpression inhibits T cell responses through a CD28-B7-dependent mechanism. J Immunol. 2006;177:1052-1061.   DOI
13 Hwang KW, Sweatt WB, Mashayekhi M, Palucki DA, Sattar H, Chuang E, Alegre ML. Transgenic expression of CTLA-4 controls lymphoproliferation in IL-2-deficient mice. J Immunol. 2004;173:5415-5424.   DOI
14 Shiratori T, Miyatake S, Ohno H, Nakaseko C, Isono K, Bonifacino JS, Saito T. Tyrosine phosphorylation controls internalization of CTLA-4 by regulating its interaction with clathrin-associated adaptor complex AP-2. Immunity. 1997;6:583-589.   DOI   ScienceOn
15 Bradshaw JD, Lu P, Leytze G, Rodgers J, Schieven GL, Bennett KL, Linsley PS, Kurtz SE. Interaction of the cytoplasmic tail of CTLA-4 (CD152) with a clathrin-associated protein is negatively regulated by tyrosine phosphorylation. Biochemistry. 1997;36:15975-15982.   DOI   ScienceOn
16 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;270:985-988.   DOI   ScienceOn
17 Lin H, Rathmell JC, Gray GS, Thompson CB, Leiden JM, Alegre ML. Cytotoxic T lymphocyte antigen 4 (CTLA4) blockade accelerates the acute rejection of cardiac allografts in CD28-deficient mice: CTLA4 can function independently of CD28. J Exp Med. 1998;188:199-204.   DOI   ScienceOn
18 Carreno BM, Bennett F, Chau TA, Ling V, Luxenberg D, Jussif J, Baroja ML, Madrenas J. CTLA-4 (CD152) can inhibit T cell activation by two different mechanisms depending on its level of cell surface expression. J Immunol. 2000;165:1352-1356.   DOI
19 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: 541-547.   DOI   ScienceOn
20 Lühder F, Höglund P, Allison JP, Benoist C, Mathis D. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) regulates the unfolding of autoimmune diabetes. J Exp Med. 1998;187:427-432   DOI   ScienceOn
21 Perrin PJ, Maldonado JH, Davis TA, June CH, Racke MK. CTLA-4 blockade enhances clinical disease and cytokine production during experimental allergic encephalomyelitis. J Immunol. 1996;157:1333-1336.
22 Tivol EA, Boyd SD, McKeon S, Borriello F, Nickerson P, Strom TB, Sharpe AH. CTLA4Ig prevents lymphoproliferation and fatal multiorgan tissue destruction in CTLA-4-deficient mice. J Immunol. 1997;158:5091-5094.
23 Gajewski TF, Fallarino F, Fields PE, Rivas F, Alegre ML. Absence of CTLA-4 lowers the activation threshold of primed CD8+ TCR-transgenic T cells: lack of correlation with Src homology domain 2-containing protein tyrosine phosphatase. J Immunol. 2001;166:3900-3907.   DOI
24 Hwang KW, Sweatt WB, Brown IE, Blank C, Gajewski TF, Bluestone JA, Alegre ML. Cutting edge: targeted ligation of CTLA-4 in vivo by membrane-bound anti-CTLA-4 antibody prevents rejection of allogeneic cells. J Immunol. 2002;169:633-637   DOI
25 Masteller EL, Chuang E, Mullen AC, Reiner SL, Thompson CB. Structural analysis of CTLA-4 function in vivo. J Immunol. 2000;164:5319-5327.   DOI
26 Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science. 1996;271:1734-1736.   DOI   ScienceOn
27 Hodi FS, Mihm MC, Soiffer RJ, Haluska FG, Butler M, Seiden MV, Davis T, Henry-Spires R, MacRae S, Willman A, Padera R, Jaklitsch MT, Shankar S, Chen TC, Korman A, Allison JP, Dranoff G. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci USA. 2003;100:4712-4717.   DOI   ScienceOn
28 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;100:8372-8377.   DOI   ScienceOn