Spontaneous apoptosis of dendritic cells is efficiently inhibited by TRAP (CD40‐ligand) and TNF‐α, but strongly enhanced by interleukin‐10

Abstract

In the lymphoid tissues, adaptive immune responses are initiated by the interaction of interdigitating dendritic cells (IDC) with naive T cells. To understand this interplay better, we used mature Langerhans cells (mLC), migrating from human epidermis, as the correlate of IDC ex vivo to evaluate the different effects of tumor necrosis factor (TNF)-alpha. TNF-related activation protein (TRAP; CD40-ligand) and interleukin-10 (IL-10) on induction or prevention of apoptotic cell death in these cells. Spontaneous decrease of mLC viability in culture was due to apoptosis, as determined by the appearance of typical morphological changes such as dilatation of the endoplasmic reticulum (ER), chromatin condensation and membrane blebbing. IL-10 strongly reduced mLC viability, whereas TRAP and TNF-alpha facilitated the survival of mLC. Spontaneous DNA fragmentation was detectable after 24 h in culture. IL-10 led to an earlier onset of DNA fragmentation, whereas TRAP and TNF-alpha delayed internucleosomal DNA cleavage. We found that IL-10-treated mLC were readily ingested and removed by macrophages. TNF-alpha and TRAP, in contrast, reduced engulfment of mLC by macrophages. Interestingly, IL-10, even at low concentrations, reverted the effects of TNF-alpha and TRAP in inhibiting mLC apoptosis. Furthermore, IL-10 led to the down-regulation of various surface antigens, especially of CD86 and CD54, whereas TNF-alpha and TRAP enhanced the expression of MHC class I and II antigens and of the accessory molecules CD40, CD54, CD80 and CD86. Taken together, these results show that mLC spontaneously undergo apoptosis in culture and that the progression of mLC to apoptosis is inhibited by TRAP and TNF-alpha, but accelerated by IL-10.

TNF-α protects dendritic cells from prostate cancer-induced apoptosis

“…38 Production of TNF-a by DC or addition of TNF-a to DC cultures greatly enhances numbers of DC and the level of their maturation as determined by the increased expression of surface molecules MHC class I and II, CD83, CD80 (B7-1), and CD86 (B7-2). 17,18,30 It has also been reported that TNF-a-stimulated DC demonstrate an 8-fold increased capacity to stimulate T cell proliferation in an MLR assay, and their antigen-presenting capacity is also increased 10 -100 fold. 17 TNF-a also promotes DC migration activity.…”

“…may act as both cell protectors and apoptosis inducers. 30,31 The influence of TNF-a influence on DC was noticed several years ago when it was suggested that TNF-a has a pivotal role in DC generation. 32,33 TNF-a has been widely used for in vitro DC production in combination with GM-CSF.…”

“…33 -35 It is also possible that TNF-a can be crucial for DC survival in cultures. 30,36 Apparently, DC are also able to produce TNF-a 35,37 and were even considered as a major source of TNF-a, in addition to macrophages. 38 Production of TNF-a by DC or addition of TNF-a to DC cultures greatly enhances numbers of DC and the level of their maturation as determined by the increased expression of surface molecules MHC class I and II, CD83, CD80 (B7-1), and CD86 (B7-2).…”

Influence of the mucosal epithelium microenvironment on Langerhans cells: Implications for the development of squamous intraepithelial lesions of the cervix

“…31,32 Moreover, by a variety of mechanisms, IL10 has been implicated in the loss of function of LC/DC 33 and the induction of apoptosis. 34 Not surprisingly, many studies have implicated IL10 in the inefficient induction of tumor immunity. [35][36][37] Consequently, the increased expression of IL10 within the microenvironment of the TZ and SILs in situ and the ability of TZ and SIL derived epithelial cells to induce IL10 in PBMC in vitro implicate this cytokine as a factor likely to influence the establishment and development of SILs.…”

Dendritic Cells Genetically Engineered to Express Fas Ligand Induce Donor-Specific Hyporesponsiveness and Prolong Allograft Survival

“…In addition, several ligand/receptor interactions have been shown to affect the outcome of FasL/Fas interaction. For example, DC survival signals expressed on T cells, such as TRANCE and CD40L, can prevent Fas-induced apoptosis (55)(56)(57).…”