After recognition of microbial products through Toll-like receptors (TLRs), immature dendritic cells (DCs) undergo a programme of maturation that eventually results in reduced endocytic capacity. However, Colin Watts and colleagues, reporting in Science, now observe that TLR ligation first acutely upregulates antigen uptake and that this is mediated by remodelling of the actin cytoskeleton.

It is well known that the DC response to microbial products triggers changes at the transcriptional level, leading ultimately to an enhanced ability to activate T cells through the upregulation of expression of MHC and co-stimulatory molecules, and a reduction in endocytic capacity. However, it has recently become clear that more-rapid responses are also induced by TLR ligation. So, the authors assessed the ability of mouse bone-marrow-derived DCs or spleen-derived DCs to take up the endocytosis marker FITC–dextran at early time points following activation with the TLR ligand lipopolysaccharide (LPS). Surprisingly, they saw that TLR ligation transiently enhanced the uptake of FITC–dextran by both cell populations, peaking after 30 to 45 minutes of treatment with LPS. To determine whether this acute stimulation of macropinocytosis also enhanced antigen presentation, they pulsed DCs with antigen, either before or at the same time as exposure to LPS, and assayed their ability to stimulate T-cell clones. Co-administration of antigen with LPS markedly enhanced the presentation of both MHC-class-I- and MHC-class-II-restricted antigen to T cells compared with administration of antigen before exposure to LPS.

Further studies using fluorescence microscopy showed that the accumulation of FITC–dextran after TLR ligation was associated with increased membrane-ruffling activity and could be inhibited by cytochalasin D, indicating that it is actin dependent. In addition, the authors observed TLR-dependent changes in the F-actin-rich structures known as podosomes, which are involved in cell migration and tissue invasion. In particular, TLR activation induced a transient destabilization of podosomes in most DCs after 30 minutes, although these structures were fully restored after 2 hours. This effect was blocked in the presence of inhibitors of two mitogen-activated protein kinases (MAPKs): MEK1 (MAPK/ERK (extracellular signal-regulated kinase) kinase 1) and SAPK2 (stress-activated protein kinase 2). Furthermore, LPS-stimulated endocytosis was also blocked by inhibitors of these MAPKs.

These findings indicate that, in response to innate immune stimuli, the actin cytoskeleton of DCs can be rapidly remodelled to mediate transient increases in actin-dependent endocytosis and enhance antigen presentation.