Consequences of Cell Death

Abstract

Cell death by necrosis is typically associated with inflammation, in contrast to apoptosis. We have identified additional distinctions between the two types of death that occur at the level of dendritic cells (DCs) and which influence the induction of immunity. DCs must undergo changes termed maturation to act as potent antigen-presenting cells. Here, we investigated whether exposure to apoptotic or necrotic cells affected DC maturation. We found that immature DCs efficiently phagocytose a variety of apoptotic and necrotic tumor cells. However, only exposure to the latter induces maturation. The mature DCs express high levels of the DC-restricted markers CD83 and lysosome-associated membrane glycoprotein (DC-LAMP) and the costimulatory molecules CD40 and CD86. Furthermore, they develop into powerful stimulators of both CD4+ and CD8+ T cells. Cross-presentation of antigens to CD8+ T cells occurs after uptake of apoptotic cells. We demonstrate here that optimal cross-presentation of antigens from tumor cells requires two steps: phagocytosis of apoptotic cells by immature DCs, which provides antigenic peptides for major histocompatibility complex class I and class II presentation, and a maturation signal that is delivered by exposure to necrotic tumor cells, their supernatants, or standard maturation stimuli, e.g., monocyte-conditioned medium. Thus, DCs are able to distinguish two types of tumor cell death, with necrosis providing a control that is critical for the initiation of immunity.

Resistance to tumour challenge after tumour laser thermotherapy is associated with a cellular immune response

“…Heat shock protein -tumour peptide complexes are taken up by antigen-processing cells like macrophages/dendritic cells, where the tumour peptides are processed and presented to T cells, eliciting an immune response (Basu et al, 2000;Sauter et al, 2000;Srivastava, 2002). In our tumour model, ILT causes a shift of HSP70 from the cytoplasm to nucleus in tumour cells, an increase in tumour-infiltrating macrophages and an increase of HSP70 in ED1-positive macrophages (Ivarsson et al, 2003).…”

“…Antitumour immunity is a complex phenomenon. There is growing evidence that dendritic cells are important for induction of immunity (Todryk et al, 1999;Basu et al, 2000;Sauter et al, 2000). Other studies have suggested that CD4 cells (Caruso et al, 1993;Kuriyama et al, 1999a, b), natural killer cells (Pierrefite-Carle et al, 1999) and antibodies (Chen et al, 1999) also may play important roles.…”

“…These modalities induce tumour cell necrosis, and an inflammatory microenvironment, which is critical for eliciting an efficient immune response (Melcher et al, 1998;Todryk et al, 1999;Sauter et al, 2000). Cell death following irradiation, 'conventional' chemotherapy and conventional hyperthermia (p42.51C) is mainly apoptotic (Cummings et al, 1997), which should give a less immunogenic response.…”

“…In our tumour model, ILT causes a shift of HSP70 from the cytoplasm to nucleus in tumour cells, an increase in tumour-infiltrating macrophages and an increase of HSP70 in ED1-positive macrophages (Ivarsson et al, 2003). It has been shown that necrotic, but not apoptotic, cell death can cause the release of HSPs (Basu et al, 2000;Sauter et al, 2000;Srivastava, 2002).…”

Nitric oxide, mitochondrial hyperpolarization, and T cell activation☆

“…Increased necrosis rates could play a central role in enhanced inflammatory responses in SLE [18]. Necrotic cell death stimulates macrophages [19] and dendritic cells [20] and leads to inflammation [15,18,21] and development of murine SLE [22]. We proposed that increased release of necrotic materials from T cells would activate macrophages and dendritic cells (DCs) and enhance their capacity to produce NO and IFN-α̣ in SLE [18].…”