Regulation of activation-induced cell death of mature T-lymphocyte populations

Abstract

Resting mature T lymphocytes are activated when triggered via their antigen-specific T-cell receptor (TCR) to elicit an appropriate immune response. In contrast, preactivated T cells may undergo activation-induced cell death (AICD) in response to the same signals. along with cell death induced by growth factor deprivation, AICD followed by the elimination of useless or potentially harmful cells preserves homeostasis, leads to the termination of cellular immune responses and ensures peripheral tolerance. T-cell apoptosis and AICD are controlled by survival cytokines such as interleukin-2 (IL-2) and by death factors such as tumor necrosis factor (TNF) and CD95 ligand (CD95L). In AICD-sensitive T cells, stimulation upregulates expression of one or several death factors, which in turn engage specific death receptors on the same or a neighboring cell. Death receptors are activated by oligomerization to rapidly assemble a number of adapter proteins and enzymes to result in an irreversible activation of proteases and nucleases that culminates in cell death by apoptosis. Increased knowledge of the molecular mechanisms that regulate AICD of lymphocytes opens new immunotherapeutic perspectives for the treatment of certain autoimmune diseases, and has implications in other areas such as transplantation medicine and AIDS research.

Activated stellate cells express the TRAIL receptor-2/death receptor-5 and undergo TRAIL-mediated apoptosis

“…13 The resolution phase of stellate cell activation is characterized by apoptosis, an activation-induced cell death phenomenon analogous to that observed in activated T cells. [17][18][19][20] The current data showing marked increases in TRAIL-DR expression by activated stellate cells suggest that TRAIL may potentially participate in the resolution phase. This concept is bolstered by the replication of our findings with the LX-2 cells in primary murine stellate cells and in the enhanced susceptibility of stellate cells from BDL mice to TRAIL.…”

“…[17][18][19] Indeed, T lymphocytes undergo activation-induced cell death as a mechanism limiting the duration of the immune response. 17,20 Activated stellate cells may also undergo an activation-induced cell death analogous to that of T cells via a Fas/Fas ligand-dependent mechanism. 21,22 These data, however, have not been replicated 23 ; more importantly, hepatocytes are very susceptible to Fas-induced cell death, limiting the therapeutic application of Fas in the liver.…”

CD95 ligand - death factor and costimulatory molecule?

“…Some reports indicate a role for FAP1, the Fas-associated phosphatase 1 and others a role of FLIP short or Bcl xl in the generation of Th2 resistance. 46 In cytotoxic T cells (and NK cells), CD95L is synthetized upon primary stimulation and then directed to and stored in secretory granules/lysosomes. 47 Besides CD95L, this type of lysosomes also contain perforins and granzymes.…”

MEF2C mediates the activation induced cell death (AICD) of macrophages

“…Apoptosis of activated macrophages may serve to restrict and focus the immune response, but it may also reduce the host defenses against infectious pathogens or contribute to immune suppression. Although our understanding of apoptosis has greatly improved in recent years, apoptosis of activated macrophages has been ill addressed in comparison with the apoptosis of lymphocytes [6][7][8]. In immune cells, apoptosis usually occurs by a particular way called activation induced cell death (AICD) [6][7][8].…”