Regulation of phosphatidylserine exposure and phagocytosis of apoptotic T lymphocytes

Abstract

In lymphocytes, an asymmetric distribution of phospholipids across the plasma membrane is maintained by an ATPdependent translocase which specifically transports aminophospholipids from the outer to the inner leaflet of the bilayer. During apoptosis, this enzyme is down-regulated and a lipid flipsite, termed the scramblase, is activated. Together, these events lead to the appearance of phosphatidylserine (PS) on the cell surface. In DO11.10 T lymphocyte hybridoma cells undergoing apoptosis, the kinetics of PS externalization are paralleled by the development of PS-sensitive phagocytosis by macrophages. This parallel is also observed when PS externalization is effected directly by application of a Ca 2+ ionophore, suggesting that PS externalization is not only necessary, but sufficient, to generate a recognition signal. The broad spectrum aspartate-directed cysteine protease (caspase) inhibitor zVAD-fmk blocks externalization of PS and terminal cell lysis after induction of apoptosis by anti-CD3 antibody, but is ineffective when apoptosis is induced in the same cells by treatment with glucocorticoid. These results suggest that apoptosis induced by glucocorticoid does not require the same zVAD-sensitive caspase steps which are required for Fas/FasL-dependent death induced by anti-CD3 antibody, and that the action of these proteases is also not required for PS externalization. Extracellular Ca 2+ is required to complete the later stages of apoptosis in DO11.10 cells, and its removal restores normal transport of PS, suggesting that down-regulation of the aminophospholipid translocase and up-regulation of the scramblase are not effected by irreversible protease cleavage.

Caspase-Independent Phosphatidylserine Exposure During Apoptosis of Primary T Lymphocytes

“…These results suggest that in primary T cells undergoing apoptosis induced by stimuli that do not involve death receptors, PS exposure and ⌬⌿m disruption do not require caspase activation. In keeping with the present data, it was shown by Verhoven et al (32) that PS exposure in D011.10 T cell hybridoma required caspase activation when apoptosis was triggered by CD95, but not when it was induced by glucocorticoids.…”

Persistence of effector memory Th1 cells is regulated by Hopx

“…5), expression of anti-apoptotic genes was upregulated by Hopx, whereas expression of pro-apoptotic genes was down-regulated. Among the anti-apoptotic genes positively regulated by Hopx and consequently down-regulated in Hopx À/À Th1 cells was Atp8a1 (APLT) encoding for an aminophospholipidtransporting enzyme important for maintaining phospholipid asymmetry and thus integrity of the cell membrane [36][37][38][39][40]. Expression of Nrn1 (neuritin 1) was also reduced in Hopx-deficient Th1 cells.…”

p21WAF1 modulates drug-induced apoptosis and cell cycle arrest in B-cell precursor acute lymphoblastic leukemia

“…However, caspase activity is not always necessary for apoptosis, and other death pathways are initiated depending on cell type and cytotoxic stimuli. 36,37 For example the apoptosis executioner, caspase-3 may stimulate the repopulation of cancer cells by increasing inflammatory signals and activating pro-survival pathways in other malignant cells. 38,39 With p21 WAF1 having an anti-apoptotic role in response to certain cytotoxic agents, inhibition of p21 WAF1 has been considered as a strategy for cancer treatment to sensitize cells toward apoptosis after chemotherapy exposure.…”