The Journal of Experimental Medicine
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Published 17 February 2004. doi:10.1084/jem.20031685
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 4, 547-557
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Deficiency of the Cyclin Kinase Inhibitor p21(WAF-1/CIP-1) Promotes Apoptosis of Activated/Memory T Cells and Inhibits Spontaneous Systemic Autoimmunity

Brian R. Lawson1, Roberto Baccala1, Jianxun Song2, Michael Croft2, Dwight H. Kono1, and Argyrios N. Theofilopoulos1

1 Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037
2 Division of Immunochemistry, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121

Address correspondence to Argyrios N. Theofilopoulos, Dept. of Immunology, The Scripps Research Institute, 10550 N. Torrey Pines Rd/IMM3, La Jolla, CA 92037. Phone: (858) 784-8135; Fax: (858) 784-8361; email: argyrio{at}scripps.edu

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.

Key Words: CDKI • lupus • replicative senescence • Fas/FasL • cell cycle

Abbreviations used in this paper: AICD, activation-induced cell death; AS, antisense; BrdU, bromodeoxyuridine; CDK, cyclin-dependent kinase; CDKI, cyclin-dependent kinase inhibitor; GN, glomerulonephritis; KLH, keyhole limpet hemocyanin; MAPK, mitogen-activated protein kinase; TNP, trinitrophenyl; TD, T-dependent.


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