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. Lawson, Roberto Baccala, Jianxun Song, Michael Croft, Dwight H. Kono, Argyrios N. Theofilopoulos

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

Abstract

A characteristic feature of systemic lupus erythematosus is the accumulation of activated/memory T and B cells. These G0/G 1-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.

Original languageEnglish (US)
Pages (from-to)547-557
Number of pages11
JournalJournal of Experimental Medicine
Volume199
Issue number4
DOIs
StatePublished - Feb 16 2004

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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