Article information
Resumen
Durante los últimos años, se ha acumulado evidencia que demuestra que la regulación del ciclo celular de las células es esencial para establecer tolerancia y suprimir autoinmunidad. Aunque la apoptosis se ha considerado un mecanismo importante en el control del desarrollo de tolerancia y autoinmunidad, la regulación del ciclo celular también constituye una vía alternativa en la prevención de la autoreactividad. Diferentes moléculas asociadas al ciclo celular actúan como supresoras de la autoinmunidad. Se ha demostrado recientemente que los inhibidores del ciclo celular p21 y p27 controlan la tolerancia de las células T, mientras que p21 también limita el desarrollo de la autoinmunidad. En esta revisión exploraremos los efectos de p21 y p27 en la inducción de la tolerancia de las células T y discutiremos la asociación entre pérdida de tolerancia y desarrollo de autoinmunidad en ratones p21–/–.
Palabras clave:
Ciclo celular/ p21/ p27/ Lupus/ Autoinmunidad/Células T
Abstract
Over the last few years, evidence has accumulated showing that cell cycle regulation of T cells is essential to establish tolerance and to suppress autoimmunity. Although apoptosis has been considered an important mechanism in the control of tolerance and autoimmunity development, cell cycle regulation also constitutes a pivotal alternative pathway in the prevention of autoreactivity. Several cell cycle-associated molecules act as autoimmunity suppressors. The cell cycle inhibitors p21 and p27 have recently been shown to control T cell tolerance, while p21 also restrains development of autoimmunity. In this review, we will explore the effects of p21 and p27 in T cell tolerance induction and discuss the association between tolerance loss and autoimmunity development in p21–/– mice.
Key words:
Cell cycle/ p21/ p27/ Lupus/ Autoimmunity/T cells
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Bibliografía
[1.]
A.A. Freitas, B. Rocha.
Population biology of lymphocytes: The flight for survival.
Annu Rev Immunol, 18 (2000), pp. 83-111
[2.]
D. Balomenos, A.C. Martínez.
Cell-cycle regulation in immunity, tolerance and autoimmunity.
Immunol Today, 21 (2000), pp. 551-555
[3.]
C.F. Arias, A. Ballesteros-Tato, M.I. García, J. Martin-Caballero, J.M. Flores, A.C. Martínez, et al.
p21CIP1/WAF1 controls proliferation of activated/memory T cells and affects homeostasis and memory T cell responses.
J Immunol, 178 (2007), pp. 2296-2306
[4.]
D. Balomenos, J. Martin-Caballero, M.I. García, I. Prieto, J.M. Flores, M. Serrano, et al.
The cell cycle inhibitor p21 controls T-cell proliferation and sex-linked lupus development.
Nat Med, 6 (2000), pp. 171-176
[5.]
C. Carvalho-Pinto, M.I. Garcia, L. Gómez, A. Ballesteros, A. Zaballos, J.M. Flores, et al.
Leukocyte attraction through the CCR5 receptor controls progress from insulitis to diabetes in non-obese diabetic mice.
Eur J Immunol, 34 (2004), pp. 548-557
[6.]
C. King, A. Ilic, K. Koelsch, N. Sarvetnick.
Homeostatic expansion of T cells during immune insufficiency generates autoimmunity.
Cell, 117 (2004), pp. 265-277
[7.]
A. Vidal, A. Koff.
Cell-cycle inhibitors: Three families united by a common cause.
Gene, 247 (2000), pp. 1-15
[8.]
A.D. Wells.
Cyclin-dependent kinases: Molecular switches controlling anergy and potential therapeutic targets for tolerance.
Semin Immunol, 19 (2007), pp. 173-179
[9.]
E.A. Rowell, A.D. Wells.
The role of cyclin-dependent kinases in T-cell development, proliferation, and function.
Crit Rev Immunol, 26 (2006), pp. 189-212
[10.]
A. Martin, J. Odajima, S.L. Hunt, P. Dubus, S. Ortega, M. Malumbres, et al.
Cdk2 is dispensable for cell cycle inhibition and tumor suppression mediated by p27(Kip1) and p21(Cip1).
Cancer Cell, 7 (2005), pp. 591-598
[11.]
D. Santamaria, C. Barriere, A. Cerqueira, S. Hunt, C. Tardy, K. Newton, et al.
Cdk1 is sufficient to drive the mammalian cell cycle.
Nature, 448 (2007), pp. 811-815
[12.]
M. Malumbres, M. Barbacid.
Cell cycle kinases in cancer.
Curr Opin Genet Dev, 17 (2007), pp. 60-65
[13.]
T. Bianchi, N. Rufer, H.R. MacDonald, M. Migliaccio.
The tumor suppressor p16Ink4a regulates T lymphocyte survival.
Oncogene, 25 (2006), pp. 4110-4115
[14.]
M.L. Fero, M. Rivkin, M. Tasch, P. Porter, C.E. Carow, E. Firpo, et al.
A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis, and female sterility in p27(Kip1)-deficient mice.
Cell, 85 (1996), pp. 733-744
[15.]
H. Kiyokawa, R.D. Kineman, K.O. Manova-Todorova, V.C. Soares, E.S. Hoffman, M. Ono, et al.
Enhanced growth of mice lacking the cyclin-dependent kinase inhibitor function of p27(Kip1).
Cell, 85 (1996), pp. 721-732
[16.]
K. Nakayama, N. Ishida, M. Shirane, A. Inomata, T. Inoue, N. Shishido, et al.
Mice lacking p27(Kip1) display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors.
Cell, 85 (1996), pp. 707-720
[17.]
L. Li, Y. Iwamoto, A. Berezovskaya, V.A. Boussiotis.
A pathway regulated by cell cycle inhibitor p27Kip1 and checkpoint inhibitor Smad3 is involved in the induction of T cell tolerance.
Nat Immunol, 7 (2006), pp. 1157-1165
[18.]
E.A. Rowell, L. Wang, W.W. Hancock, A.D. Wells.
The cyclin-dependent kinase inhibitor p27kip1 is required for transplantation tolerance induced by costimulatory blockade.
J Immunol, 177 (2006), pp. 5169-5176
[20.]
N. Bidere, H.C. Su, M.J. Lenardo.
Genetic disorders of programmed cell death in the immune system.
Annu Rev Immunol, 24 (2006), pp. 321-352
[21.]
S.E. Straus, M. Sneller, M.J. Lenardo, J.M. Puck, W. Strober.
An inherited disorder of lymphocyte apoptosis: The autoimmune lymphoproliferative syndrome.
Ann Intern Med, 130 (1999), pp. 591-601
[22.]
K.G. Smith, A. Strasser, D.L. Vaux.
CrmA expression in T lymphocytes of transgenic mice inhibits CD95 (Fas/APO-1)-transduced apoptosis, but does not cause lymphadenopathy or autoimmune disease.
EMBO J, 15 (1996), pp. 5167-5176
[23.]
K. Newton, A.W. Harris, M.L. Bath, K.G. Smith, A. Strasser.
A dominant interfering mutant of FADD/MORT1 enhances deletion of autoreactive thymocytes and inhibits proliferation of mature T lymphocytes.
EMBO J, 17 (1998), pp. 706-718
[24.]
K. Newton, C. Kurts, A.W. Harris, A. Strasser.
Effects of a dominant interfering mutant of FADD on signal transduction in activated T cells.
Curr Biol, 11 (2001), pp. 273-276
[25.]
J. Zhang, D. Cado, A. Chen, N.H. Kabra, A. Winoto.
Fas-mediated apoptosis and activation-induced T-cell proliferation are defective in mice lacking FADD/Mort1.
Nature, 392 (1998), pp. 296-300
[26.]
N.J. Kennedy, T. Kataoka, J. Tschopp, R.C. Budd.
Caspase activation is required for T cell proliferation.
J Exp Med, 190 (1999), pp. 1891-1896
[27.]
H.J. Chun, L. Zheng, M. Ahmad, J. Wang, C.K. Speirs, R.M. Siegel, et al.
Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency.
Nature, 419 (2002), pp. 395-399
[28.]
H. Su, N. Bidere, L. Zheng, A. Cubre, K. Sakai, J. Dale, et al.
Requirement for caspase-8 in NF-κB activation by antigen receptor.
Science, 307 (2005), pp. 1465-1468
[29.]
L. Salmena, B. Lemmers, A. Hakem, E. Matysiak-Zablocki, K. Murakami, P.Y. Au, et al.
Essential role for caspase 8 in T-cell homeostasis and T-cell-mediated immunity.
Genes Dev, 17 (2003), pp. 883-895
[30.]
J.C. Rathmell, C.B. Thompson.
Pathways of apoptosis in lymphocyte development, homeostasis, and disease.
Cell, 109 (2002), pp. S97-S107
[31.]
K.A. Fortner, R.C. Budd.
The death receptor Fas (CD95/APO-1) mediates the deletion of T lymphocytes undergoing homeostatic proliferation.
J Immunol, 175 (2005), pp. 4374-4382
[32.]
D. Balomenos, R. Rumold, A.N. Theofilopoulos.
The proliferative in vivo activities of lpr double-negative T cells and the primary role of p59fyn in their activation and expansion.
J Immunol, 159 (1997), pp. 2265-2273
[33.]
F. Le Deist, J.F. Emile, F. Rieux-Laucat, M. Benkerrou, I. Roberts, N. Brousse, et al.
Clinical, immunological, and pathological consequences of Fas-deficient conditions.
Lancet, 348 (1996), pp. 719-723
[34.]
M.S. Lim, S.E. Straus, J.K. Dale, T.A. Fleisher, M. Stetler-Stevenson, W. Strober, et al.
Pathological findings in human autoimmune lymphoproliferative syndrome.
Am J Pathol, 153 (1998), pp. 1541-1550
[35.]
L. Van Parijs, D.A. Peterson, A.K. Abbas.
The Fas/Fas ligand pathway and Bcl-2 regulate T cell responses to model self and foreign antigens.
Immunity, 8 (1998), pp. 265-274
[36.]
A.L. Gartel, A.L. Tyner.
The role of the cyclin-dependent kinase inhibitor p21 in apoptosis.
Mol Cancer Ther, 1 (2002), pp. 639-649
[37.]
B.R. Lawson, R. Baccala, J. Song, M. Croft, D.H. Kono, A.N. Theofilopoulos.
Deficiency of the cyclin kinase inhibitor p21(WAF-1/CIP-1) promotes apoptosis of activated/memory T cells and inhibits spontaneous systemic autoimmunity.
J Exp Med, 199 (2004), pp. 547-557
[38.]
A. Suzuki, Y. Tsutomi, K. Akahane, T. Araki, M. Miura.
Resistance to Fas-mediated apoptosis: activation of caspase 3 is regulated by cell cycle regulator p21WAF1 and IAP gene family ILP.
Oncogene, 17 (1998), pp. 931-939
[39.]
R. Hingorani, B. Bi, T. Dao, Y. Bae, A. Matsuzawa.
Crispe IN. CD95/Fas signaling in T lymphocytes induces the cell cycle control protein p21cip-1/WAF-1, which promotes apoptosis.
J Immunol, 164 (2000), pp. 4032-4036
[40.]
R. Fotedar, H. Brickner, N. Saadatmandi, T. Rousselle, L. Diederich, A. Munshi, et al.
Effect of p21waf1/cip1 transgene on radiation induced apoptosis in T cells.
Oncogene, 18 (1999), pp. 3652-3658
[41.]
B.R. Lawson, D.H. Kono, A.N. Theofilopoulos.
Deletion of p21 (WAF- 1/Cip1) does not induce systemic autoimmunity in female BXSB mice.
J Immunol, 168 (2002), pp. 5928-5932
[42.]
C. Goulvestre, C. Chereau, C. Nicco, L. Mouthon, B. Weill, F. Batteux.
A mimic of p21WAF1/CIP1 ameliorates murine lupus.
J Immunol, 175 (2005), pp. 6959-6967
[43.]
J.M. Salvador, M.C. Hollander, A.T. Nguyen, J.B. Kopp, L. Barisoni, J.K. Moore, et al.
Mice lacking the p53-effector gene Gadd45a develop a lupuslike syndrome.
Immunity, 16 (2002), pp. 499-508
[44.]
M. Murga, O. Fernandez-Capetillo, S.J. Field, B. Moreno, L.R. Borlado, Y. Fujiwara, et al.
Mutation of E2F2 in mice causes enhanced T lymphocyte proliferation, leading to the development of autoimmunity.
Immunity, 15 (2001), pp. 959-970
[45.]
A.K. Abbas.
The control of T cell activation vs. tolerance.
Autoimmun Rev, 2 (2003), pp. 115-118
[46.]
V.R. Moulton, N.D. Bushar, D.B. Leeser, D.S. Patke, D.L. Farber.
Divergent generation of heterogeneous memory CD4 T cells.
J Immunol, 177 (2006), pp. 869-876
[47.]
H. Hu, G. Huston, D. Duso, N. Lepak, E. Roman, S.L. Swain.
CD4+ T cell effectors can become memory cells with high efficiency and without further division.
Nat Immunol, 2 (2001), pp. 705-710
[48.]
E.L. Pearce, H. Shen.
Making sense of inflammation, epigenetics, and memory CD8+ T-cell differentiation in the context of infection.
Immunol Rev, 211 (2006), pp. 197-202
[49.]
E.A. Rowell, M.C. Walsh, A.D. Wells.
Opposing roles for the cyclindependent kinase inhibitor p27kip1 in the control of CD4+ T cell proliferation and effector function.
J Immunol, 174 (2005), pp. 3359-3368
[50.]
L.J. Appleman, A.A. van Puijenbroek, K.M. Shu, L.M. Nadler, V.A. Boussiotis.
CD28 costimulation mediates down-regulation of p27kip1 and cell cycle progression by activation of the PI3K/PKB signaling pathway in primary human T cells.
J Immunol, 168 (2002), pp. 2729-2736
[51.]
S. Zhang, V.A. Lawless, M.H. Kaplan.
Cytokine-stimulated T lymphocyte proliferation is regulated by p27Kip1.
J Immunol, 165 (2000), pp. 6270-6277
[52.]
C.E. Rudd.
Cell cycle ‘check points’ T cell anergy.
Nat Immunol, 7 (2006), pp. 1130-1132
[53.]
R. Shen, M.H. Kaplan.
The homeostasis but not the differentiation of T cells is regulated by p27(Kip1).
J Immunol, 169 (2002), pp. 714-721
[54.]
A.E. Bygrave, K.L. Rose, J. Cortes-Hernandez, J. Warren, R.J. Rigby, H.T. Cook, et al.
Spontaneous autoimmunity in 129 and C57BL/6 miceimplications for autoimmunity described in gene-targeted mice.
PLoS Biol, 2 (2004), pp. E243
[55.]
Z.M. Sthoeger, H. Zinger, E. Mozes.
Beneficial effects of the anti-oestrogen tamoxifen on systemic lupus erythematosus of (NZBxNZW)F1 female mice are associated with specific reduction of IgG3 autoantibodies.
Ann Rheum Dis, 62 (2003), pp. 341-346
[56.]
R.W. McMurray.
Estrogen, prolactin, and autoimmunity: actions and interactions.
Int Immunopharmacol, 1 (2001), pp. 995-1008
[57.]
M.L. Santiago-Raber, B.R. Lawson, W. Dummer, M. Barnhouse, S. Koundouris, C.B. Wilson, et al.
Role of cyclin kinase inhibitor p21 in systemic autoimmunity.
J Immunol, 167 (2001), pp. 4067-4074
[58.]
D.A. Mitchell, M.C. Pickering, J. Warren, L. Fossati-Jimack, J. Cortes- Hernandez, H.T. Cook, et al.
C1q deficiency and autoimmunity: the effects of genetic background on disease expression.
J Immunol, 168 (2002), pp. 2538-2543
[59.]
J. Cortes-Hernandez, L. Fossati-Jimack, F. Petry, M. Loos, S. Izui, M.J. Walport, et al.
Restoration of C1q levels by bone marrow transplantation attenuates autoimmune disease associated with C1q deficiency in mice.
Eur J Immunol, 34 (2004), pp. 3713-3722
[60.]
S. Vidal, D.H. Kono, A.N. Theofilopoulos.
Loci predisposing to autoimmunity in MRL-Fas lpr and C57BL/6-Faslpr mice.
J Clin Invest, 101 (1998), pp. 696-702
[61.]
Z. Grossman, W.E. Paul.
Self-tolerance: Context dependent tuning of T cell antigen recognition.
Semin Immunol, 12 (2000), pp. 197-203
[62.]
J. Wang, M.J. Lenardo.
Molecules involved in cell death and peripheral tolerance.
Curr Opin Immunol, 9 (1997), pp. 818-825
[63.]
A. Strasser, S. Whittingham, D.L. Vaux, M.L. Bath, J.M. Adams, S. Cory, et al.
Enforced BCL2 expression in B-lymphoid cells prolongs antibody responses and elicits autoimmune disease.
Proc Natl Acad Sci USA, 88 (1991), pp. 8661-8665
[64.]
P. Bouillet, D. Metcalf, D.C. Huang, D.M. Tarlinton, T.W. Kay, F. Kontgen, et al.
Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity.
Science, 286 (1999), pp. 1735-1738
[65.]
L. Liu, E. Tran, Y. Zhao, Y. Huang, R. Flavell, B. Lu.
Gadd45 ‚and Gadd45 γ are critical for regulating autoimmunity.
J Exp Med, 202 (2005), pp. 1341-1347
[66.]
R. Merino, T. Shibata, S. De Kossodo, S. Izui.
Differential effect of the autoimmune Yaa and lpr genes on the acceleration of lupus-like syndrome in MRL/MpJ mice.
Eur J Immunol, 19 (1989), pp. 2131-2137
[67.]
S. Izui, R. Merino, L. Fossati, M. Iwamoto.
The role of the Yaa gene in lupus syndrome.
Int Rev Immunol, 11 (1994), pp. 211-230
[68.]
L. Fossati, E.S. Sobel, M. Iwamoto, P.P.L. Cohen, R.A. Eisenberg, S. Izui.
The Yaa gene-mediated acceleration of murine lupus: Yaa- T cells from non-autoimmune mice collaborate with Yaa+ B cells to produce lupus autoantibodies in vivo.
Eur J Immunol, 25 (1995), pp. 3412-3417
[69.]
M. Woo, R. Hakem, C. Furlonger, A. Hakem, G.S. Duncan, T. Sasaki, et al.
Caspase-3 regulates cell cycle in B cells: A consequence of substrate specificity.
Nat Immunol, 4 (2003), pp. 1016-1022
[70.]
J. Brugarolas, C. Chandrasekaran, J.I. Gordon, D. Beach, T. Jacks, G.J. Hannon.
Radiation-induced cell cycle arrest compromised by p21 deficiency.
Nature, 377 (1995), pp. 552-557
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