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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.

Lawson BR, Baccala R, Song J, Croft M, Kono DH, Theofilopoulos AN - J. Exp. Med. (2004)

Bottom Line: 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.Thus, modulation of the cell cycle pathway may be a novel approach to reduce apoptosis-resistant pathogenic lymphocytes and to ameliorate systemic autoimmunity.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.

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.

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Representative distribution of G0- versus G1-phase in CD4+CD44hi T cells. Splenocytes from 3-mo-old mice (n = 4 animals/group) were stained with antibodies to CD4 and CD44, followed by sequential incubation with Hoechst 33342 (DNA-binding dye) and Pyronin Y (RNA-binding dye) and analyzed by flow cytometry. Pyronin Y staining of G0/G1-phase CD4+CD44hi T cells from p21−/− and p21+/+ BXSB mice is shown (P < 0.05).
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fig2: Representative distribution of G0- versus G1-phase in CD4+CD44hi T cells. Splenocytes from 3-mo-old mice (n = 4 animals/group) were stained with antibodies to CD4 and CD44, followed by sequential incubation with Hoechst 33342 (DNA-binding dye) and Pyronin Y (RNA-binding dye) and analyzed by flow cytometry. Pyronin Y staining of G0/G1-phase CD4+CD44hi T cells from p21−/− and p21+/+ BXSB mice is shown (P < 0.05).

Mentions: To further define the in vivo cycling characteristics of p21-deficient CD4+CD44hi T cells, the frequency of cells in G0- versus G1-phase was determined by the RNA indicator dye Pyronin Y. Strikingly, the frequency of Pyronin Yhi (G1-phase) CD4+CD44hi T cells was significantly higher in p21-deficient mice versus BXSB male controls (86.2 ± 2.4% vs. 44.3 ± 5.8%; Fig. 2, P < 0.05).


Deficiency of the cyclin kinase inhibitor p21(WAF-1/CIP-1) promotes apoptosis of activated/memory T cells and inhibits spontaneous systemic autoimmunity.

Lawson BR, Baccala R, Song J, Croft M, Kono DH, Theofilopoulos AN - J. Exp. Med. (2004)

Representative distribution of G0- versus G1-phase in CD4+CD44hi T cells. Splenocytes from 3-mo-old mice (n = 4 animals/group) were stained with antibodies to CD4 and CD44, followed by sequential incubation with Hoechst 33342 (DNA-binding dye) and Pyronin Y (RNA-binding dye) and analyzed by flow cytometry. Pyronin Y staining of G0/G1-phase CD4+CD44hi T cells from p21−/− and p21+/+ BXSB mice is shown (P < 0.05).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211831&req=5

fig2: Representative distribution of G0- versus G1-phase in CD4+CD44hi T cells. Splenocytes from 3-mo-old mice (n = 4 animals/group) were stained with antibodies to CD4 and CD44, followed by sequential incubation with Hoechst 33342 (DNA-binding dye) and Pyronin Y (RNA-binding dye) and analyzed by flow cytometry. Pyronin Y staining of G0/G1-phase CD4+CD44hi T cells from p21−/− and p21+/+ BXSB mice is shown (P < 0.05).
Mentions: To further define the in vivo cycling characteristics of p21-deficient CD4+CD44hi T cells, the frequency of cells in G0- versus G1-phase was determined by the RNA indicator dye Pyronin Y. Strikingly, the frequency of Pyronin Yhi (G1-phase) CD4+CD44hi T cells was significantly higher in p21-deficient mice versus BXSB male controls (86.2 ± 2.4% vs. 44.3 ± 5.8%; Fig. 2, P < 0.05).

Bottom Line: 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.Thus, modulation of the cell cycle pathway may be a novel approach to reduce apoptosis-resistant pathogenic lymphocytes and to ameliorate systemic autoimmunity.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.

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.

Show MeSH
Related in: MedlinePlus