Apoptosis‐induced inhibition of CD1d‐mediated antigen presentation: different roles for caspases and signal transduction pathways

Abstract

SummaryThe stimulation of programmed cell death can either enhance or inhibit antigen presentation by classic major histocompatibility complex molecules. In the current study, we report that the induction of apoptosis by topoisomerase I inhibition or elevation of intracellular ceramide levels substantially impairs CD1d-mediated antigen presentation. In the former case, such a reduction occurred via the regulation of both the p38 mitogen-activated protein kinases and protein kinase C d signal transduction pathways as well as the caspase cascade, whereas the latter was p38-(but not caspase)-dependent. Confocal microscopic analysis showed an altered intracellular distribution of CD1d following the inhibition topoisomerase I or by an increase in intracellular ceramide levels, that was prevented by p38 and caspase inhibitors. Thus, the induction of apoptosis in antigen presenting cells severely compromises CD1d-mediated antigen presentation by multiple mechanisms.

Anthrax Lethal Toxin Impairs CD1d-Mediated Antigen Presentation by Targeting the Extracellular Signal-Related Kinase 1/2 Mitogen-Activated Protein Kinase Pathway

“…This suggests that the functional expression of both CD1d and MHC class II molecules is altered by LT and confirms a previous study analyzing the latter antigen presentation system (2). These data are also consistent with our prior reports suggesting that MHC class II-and CD1d-mediated antigen presentations are similarly regulated by specific cell signaling pathways (10,19,20).…”

“…LMTK-CD1d1 cells were treated with vehicle or the indicated concentrations of PA, LF, or LT (PA plus LF). The cells were lysed in lysis buffer containing Complete protease inhibitor tablets (Roche Diagnostics, Indianapolis, IN) as described previously (20). Equal amounts of protein were loaded into each well, resolved on a 10% SDS-polyacrylamide gel, and subsequently transferred to a polyvinylidene difluoride membrane (Millipore, Bedford, MA).…”

“…Bacillus anthracis via LT is capable of disrupting MAPK signaling pathways that are important for dendritic cell and macrophage function (2,3,32). These pathways include those we have shown to regulate CD1d-mediated antigen presentation (10,20,25,34).…”

Cell Signaling Pathways That Regulate Antigen Presentation

“…Interestingly, p38 inhibits (whereas ERK promotes) the differentiation of monocytes into DCs (40). As will be mentioned below, p38 and ERK have similar reciprocal control over CD1d-mediated Ag presentation (41-43). Unstimulated DCs have a basal level of p38 that is enhanced following stimulation with anisomycin, a drug that activates both p38 and JNK (44).…”

“…However, this does not only occur in a virus infection. Inducing apoptosis in CD1d+ APCs stimulates p38 activation; not surprisingly, these cells are poorer stimulators of NKT cells (41). Interestingly, another group has looked at Ag presentation by Group 1 CD1 molecules.…”