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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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T cell senescence and p21 in systemic autoimmunity. In lupus-prone mice, the accumulated activated/memory CD4+ T cells are in a state resembling replicative senescence. We hypothesize that repeated stimulation of CD4+ T cells (depicted by the hypothetical movement of cells from the memory to effector compartments) by self-antigens (Ag) leads to resistance to proliferation and apoptosis (senescent-like cell), due in large part to increased levels of CDKIs. Senescent cells are metabolically active and can produce proinflammatory cytokines. As shown in this work, the gradual accumulation of these activated/memory phenotype CD4+ T cells and subsequent development of autoimmunity is dependent on p21. Furthermore, our data indicate that the fraction of activated/memory CD4+CD44hi T cells that escape AICD in wild-type autoimmune mice (because of increased CDKIs) do not accumulate in G0/G1-phase in p21-deficient mice; instead, they proliferate and become susceptible to Fas-mediated apoptosis. Thus, the lack of p21 appears to restore homeostasis of autoreactive CD4+CD44hi T cells by preventing their transition to a senescent-like state.
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fig7: T cell senescence and p21 in systemic autoimmunity. In lupus-prone mice, the accumulated activated/memory CD4+ T cells are in a state resembling replicative senescence. We hypothesize that repeated stimulation of CD4+ T cells (depicted by the hypothetical movement of cells from the memory to effector compartments) by self-antigens (Ag) leads to resistance to proliferation and apoptosis (senescent-like cell), due in large part to increased levels of CDKIs. Senescent cells are metabolically active and can produce proinflammatory cytokines. As shown in this work, the gradual accumulation of these activated/memory phenotype CD4+ T cells and subsequent development of autoimmunity is dependent on p21. Furthermore, our data indicate that the fraction of activated/memory CD4+CD44hi T cells that escape AICD in wild-type autoimmune mice (because of increased CDKIs) do not accumulate in G0/G1-phase in p21-deficient mice; instead, they proliferate and become susceptible to Fas-mediated apoptosis. Thus, the lack of p21 appears to restore homeostasis of autoreactive CD4+CD44hi T cells by preventing their transition to a senescent-like state.

Mentions: This cellular activation model provides a possible explanation for the accumulation of activated/memory phenotype CD4+ T cells in lupus (Fig. 7). We hypothesize that genetic susceptibility predisposes lupus T cells to hyperrespond through a variety of mechanisms, such as increased antigen presentation or lack of regulatory signaling. Many of these mechanisms have been revealed recently by analyses of spontaneous as well as gene knockout and transgenic mice with lupuslike disease (46, 47). This enhanced activation, together with continuous stimulation by ever-present self-antigens, will lead to repeated interconversions of T cells from effector to memory and vice versa. Selection of high affinity memory T cells results in increased MAPK signaling, induction of CDKIs, and finally accumulation of memory phenotype T cells that are replication and apoptosis resistant. Potential experimental analogies are resistance to cell cycle progression of T cells cultured for prolonged periods with anti-CD3 antibody (48) and high concentrations of superantigen (49) or specific antigen (50). In further support of this hypothesis, HLA-A1–specific T cells repeatedly stimulated in vitro with antigen to emulate possible autoimmune responses converted to effector/memory phenotype cells resistant to CD95-mediated AICD (51). As discussed here, absence of the pancyclin inhibitor p21 reduces the likelihood of cells attaining this G0/G1 arrested state, and their accumulation. It is significant that despite the multiple pancyclin inhibitors (p21, p27, and p57), deletion of p21 can accomplish this effect, implying that functional redundancy among these molecules is only partial.


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)

T cell senescence and p21 in systemic autoimmunity. In lupus-prone mice, the accumulated activated/memory CD4+ T cells are in a state resembling replicative senescence. We hypothesize that repeated stimulation of CD4+ T cells (depicted by the hypothetical movement of cells from the memory to effector compartments) by self-antigens (Ag) leads to resistance to proliferation and apoptosis (senescent-like cell), due in large part to increased levels of CDKIs. Senescent cells are metabolically active and can produce proinflammatory cytokines. As shown in this work, the gradual accumulation of these activated/memory phenotype CD4+ T cells and subsequent development of autoimmunity is dependent on p21. Furthermore, our data indicate that the fraction of activated/memory CD4+CD44hi T cells that escape AICD in wild-type autoimmune mice (because of increased CDKIs) do not accumulate in G0/G1-phase in p21-deficient mice; instead, they proliferate and become susceptible to Fas-mediated apoptosis. Thus, the lack of p21 appears to restore homeostasis of autoreactive CD4+CD44hi T cells by preventing their transition to a senescent-like state.
© Copyright Policy
Related In: Results  -  Collection

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

fig7: T cell senescence and p21 in systemic autoimmunity. In lupus-prone mice, the accumulated activated/memory CD4+ T cells are in a state resembling replicative senescence. We hypothesize that repeated stimulation of CD4+ T cells (depicted by the hypothetical movement of cells from the memory to effector compartments) by self-antigens (Ag) leads to resistance to proliferation and apoptosis (senescent-like cell), due in large part to increased levels of CDKIs. Senescent cells are metabolically active and can produce proinflammatory cytokines. As shown in this work, the gradual accumulation of these activated/memory phenotype CD4+ T cells and subsequent development of autoimmunity is dependent on p21. Furthermore, our data indicate that the fraction of activated/memory CD4+CD44hi T cells that escape AICD in wild-type autoimmune mice (because of increased CDKIs) do not accumulate in G0/G1-phase in p21-deficient mice; instead, they proliferate and become susceptible to Fas-mediated apoptosis. Thus, the lack of p21 appears to restore homeostasis of autoreactive CD4+CD44hi T cells by preventing their transition to a senescent-like state.
Mentions: This cellular activation model provides a possible explanation for the accumulation of activated/memory phenotype CD4+ T cells in lupus (Fig. 7). We hypothesize that genetic susceptibility predisposes lupus T cells to hyperrespond through a variety of mechanisms, such as increased antigen presentation or lack of regulatory signaling. Many of these mechanisms have been revealed recently by analyses of spontaneous as well as gene knockout and transgenic mice with lupuslike disease (46, 47). This enhanced activation, together with continuous stimulation by ever-present self-antigens, will lead to repeated interconversions of T cells from effector to memory and vice versa. Selection of high affinity memory T cells results in increased MAPK signaling, induction of CDKIs, and finally accumulation of memory phenotype T cells that are replication and apoptosis resistant. Potential experimental analogies are resistance to cell cycle progression of T cells cultured for prolonged periods with anti-CD3 antibody (48) and high concentrations of superantigen (49) or specific antigen (50). In further support of this hypothesis, HLA-A1–specific T cells repeatedly stimulated in vitro with antigen to emulate possible autoimmune responses converted to effector/memory phenotype cells resistant to CD95-mediated AICD (51). As discussed here, absence of the pancyclin inhibitor p21 reduces the likelihood of cells attaining this G0/G1 arrested state, and their accumulation. It is significant that despite the multiple pancyclin inhibitors (p21, p27, and p57), deletion of p21 can accomplish this effect, implying that functional redundancy among these molecules is only partial.

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