Deficiency of the Cyclin Kinase Inhibitor P21(WAF-1/CIP-1) Promotes Apoptosis of Activated/memory T Cells and Inhibits Spontaneous Systemic Autoimmunity

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2004 Feb 19

PMID 14970181

Citations 25

Authors

Brian R Lawson

Roberto Baccala

Jianxun Song

Michael Croft

Dwight H Kono

Argyrios N Theofilopoulos

Affiliations

Soon will be listed here.

Abstract

A characteristic feature of systemic lupus erythematosus is the accumulation of activated/memory T and B cells. These G0/G1-arrested cells express high levels of cyclin-dependent kinase inhibitors such as p21, are resistant to proliferation and apoptosis, and produce large amounts of proinflammatory cytokines. Herein, we show that ablation of p21 in lupus-prone mice allows these cells to reenter the cell cycle and undergo apoptosis, leading to autoimmune disease reduction. Absence of p21 resulted in enhanced Fas/FasL-mediated activation-induced T cell death, increased activation of procaspases 8 and 3, and loss of mitochondrial transmembrane potential. Increased apoptosis was also associated with p53 up-regulation and a modest shift in the ratio of Bax/Bcl-2 toward the proapoptotic Bax. Proliferation and apoptosis of B cells were also increased in p21-/- lupus mice. Thus, modulation of the cell cycle pathway may be a novel approach to reduce apoptosis-resistant pathogenic lymphocytes and to ameliorate systemic autoimmunity.

Citing Articles

c-Myc uses Cul4b to preserve genome integrity and promote antiviral CD8 T cell immunity.

Dar A, Kim D, Gordon S, Klinzing K, Rosen S, Guha I Nat Commun. 2023; 14(1):7098.

PMID: 37925424 PMC: 10625626. DOI: 10.1038/s41467-023-42765-7.

TP53 and p21 (CDKN1A) polymorphisms and the risk of systemic lupus erythematosus.

Macedo J, Silva A, Pinto A, Landeira L, Portari E, Santos-Reboucas C Adv Rheumatol. 2023; 63(1):43.

PMID: 37605254 DOI: 10.1186/s42358-023-00320-4.

p21 produces a bioactive secretome that places stressed cells under immunosurveillance.

Sturmlechner I, Zhang C, Sine C, van Deursen E, Jeganathan K, Hamada N Science. 2021; 374(6567):eabb3420.

PMID: 34709885 PMC: 8985214. DOI: 10.1126/science.abb3420.

Differentially Expressed Gene Pathways in the Conjunctiva of Sjögren Syndrome Keratoconjunctivitis Sicca.

de Paiva C, Trujillo-Vargas C, Schaefer L, Yu Z, Britton R, Pflugfelder S Front Immunol. 2021; 12:702755.

PMID: 34349764 PMC: 8326832. DOI: 10.3389/fimmu.2021.702755.

DNA Damage Response in the Adaptive Arm of the Immune System: Implications for Autoimmunity.

Manolakou T, Verginis P, Boumpas D Int J Mol Sci. 2021; 22(11).

PMID: 34072535 PMC: 8198144. DOI: 10.3390/ijms22115842.

References

Gmelig-Meyling F, Dawisha S, Steinberg A . Assessment of in vivo frequency of mutated T cells in patients with systemic lupus erythematosus. J Exp Med. 1992; 175(1):297-300. PMC: 2119089. DOI: 10.1084/jem.175.1.297. View

Smerdon R, Peakman M, Hussain M, Alviggi L, Watkins P, Leslie R . Increase in simultaneous coexpression of naive and memory lymphocyte markers at diagnosis of IDDM. Diabetes. 1993; 42(1):127-33. DOI: 10.2337/diab.42.1.127. View

Boehme S, Lenardo M . Propriocidal apoptosis of mature T lymphocytes occurs at S phase of the cell cycle. Eur J Immunol. 1993; 23(7):1552-60. DOI: 10.1002/eji.1830230724. View

Gilbert K, Weigle W . Th1 cell anergy and blockade in G1a phase of the cell cycle. J Immunol. 1993; 151(3):1245-54. View

Noda A, Ning Y, Venable S, Smith J . Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen. Exp Cell Res. 1994; 211(1):90-8. DOI: 10.1006/excr.1994.1063. View

Miethke T, Wahl C, GAUS H, Heeg K, Wagner H . Exogenous superantigens acutely trigger distinct levels of peripheral T cell tolerance/immunosuppression: dose-response relationship. Eur J Immunol. 1994; 24(8):1893-902. DOI: 10.1002/eji.1830240827. View

Sprent J, Tough D . Lymphocyte life-span and memory. Science. 1994; 265(5177):1395-400. DOI: 10.1126/science.8073282. View

Ahmed R, Gray D . Immunological memory and protective immunity: understanding their relation. Science. 1996; 272(5258):54-60. DOI: 10.1126/science.272.5258.54. View

Andris F, Van Mechelen M, De Mattia F, Baus E, Urbain J, Leo O . Induction of T cell unresponsiveness by anti-CD3 antibodies occurs independently of co-stimulatory functions. Eur J Immunol. 1996; 26(5):1187-95. DOI: 10.1002/eji.1830260534. View

10.

Arbogast A, Boutet S, Phelouzat M, Plastre O, Quadri R, Proust J . Failure of T lymphocytes from elderly humans to enter the cell cycle is associated with low Cdk6 activity and impaired phosphorylation of Rb protein. Cell Immunol. 1999; 197(1):46-54. DOI: 10.1006/cimm.1999.1550. View

11.

Green D, Scott D . Activation-induced apoptosis in lymphocytes. Curr Opin Immunol. 1994; 6(3):476-87. DOI: 10.1016/0952-7915(94)90130-9. View

12.

Fotedar R, Flatt J, Gupta S, Margolis R, Fitzgerald P, Messier H . Activation-induced T-cell death is cell cycle dependent and regulated by cyclin B. Mol Cell Biol. 1995; 15(2):932-42. PMC: 231980. DOI: 10.1128/MCB.15.2.932. View

13.

Marshall C . Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell. 1995; 80(2):179-85. DOI: 10.1016/0092-8674(95)90401-8. View

14.

Prudhomme G, Kono D, Theofilopoulos A . Quantitative polymerase chain reaction analysis reveals marked overexpression of interleukin-1 beta, interleukin-1 and interferon-gamma mRNA in the lymph nodes of lupus-prone mice. Mol Immunol. 1995; 32(7):495-503. DOI: 10.1016/0161-5890(95)00024-9. View

15.

Deng C, Zhang P, Harper J, Elledge S, Leder P . Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control. Cell. 1995; 82(4):675-84. DOI: 10.1016/0092-8674(95)90039-x. View

16.

Dayal A, Kammer G . The T cell enigma in lupus. Arthritis Rheum. 1996; 39(1):23-33. DOI: 10.1002/art.1780390104. View

17.

Campisi J . Replicative senescence: an old lives' tale?. Cell. 1996; 84(4):497-500. DOI: 10.1016/s0092-8674(00)81023-5. View

18.

Hobeika A, Etienne W, Torres B, Johnson H, Subramaniam P . IFN-gamma induction of p21(WAF1) is required for cell cycle inhibition and suppression of apoptosis. J Interferon Cytokine Res. 2000; 19(12):1351-61. DOI: 10.1089/107999099312812. View

19.

Balomenos D, Martin-Caballero J, Garcia M, Prieto I, Flores J, Serrano M . The cell cycle inhibitor p21 controls T-cell proliferation and sex-linked lupus development. Nat Med. 2000; 6(2):171-6. DOI: 10.1038/72272. View

20.

Wither J, Paterson A, Vukusic B . Genetic dissection of B cell traits in New Zealand black mice. The expanded population of B cells expressing up-regulated costimulatory molecules shows linkage to Nba2. Eur J Immunol. 2000; 30(2):356-65. DOI: 10.1002/1521-4141(200002)30:2<356::AID-IMMU356>3.0.CO;2-H. View