Enhanced Dendritic Cell Antigen Capture via Toll-Like Receptor-Induced Actin Remodeling

Speaker: 錢鵬如                              Date: 11/3/2004; 15:00-16:00

Commentator: 黎煥耀 老師                     Place: Room 601

Abstract:

   Dendritic cells (DC) are professional antigen-presenting cells (APC) involved in the initiation of both innate and adaptive immunity. Recognition of microbial products through Toll-like receptors (TLRs) triggers dendritic cell maturation and results in the induction of costimulatory molecules and the enhancement of antigen presentation on both class I and class II MHC molecules for naïve T cell activation (1). Nevertheless, many of these adaptations take several hours to become evident. In particular, it is not known how mature DCs down-regulate endocytic capacity dramatically upon encounter with a pathogen. In this paper, the authors         investigated early events in murine bone marrow-derived DCs (BMDCs) and spleen-derived DCs (SDCs) following TLR activation. They found both types of DC stimulated with different TLR ligands transiently enhanced endocytosis and FITC-dextran accumulation (macropinosomes). By using cytochalasin D, which depolymerizes actin filaments, abolished LPS-stimulated FITC-dextran uptake by DCs. These results showed that down-regulation of DC endocytosis was preceded by a short-term enhancement of actin-dependent endocytic capacity. Furthermore, coadministration of antigen with LPS resulted in significantly enhanced antigen presentation and stimulation of T cell activation. TLR activation in DCs also induced dramatic effects on F-actin-rich structures called podosomes. Actinomycin D, which blocks de novo gene transcription, had no effects on enhanced endocytosis and podosome disassembly in LPS-stimulated DCs. Interestingly, both ERK1/2 and p38 MAP kinases were activated in DCs stimulated with LPS, and kinetics similar to the actin rearrangements were observed. Combination of the inhibitors of these two MAP kinases blocked podosome disassembly and antigen uptake of LPS-stimulated DC. According to these results, enhanced antigen capture of DC by endocytosis and podosome disassembly occur at early stage after TLR activation and MAP kinases are involved in this phenomena.

References:

1.      Granucci, F. et al. Eur. J. Immunol. 31: 2539-2546, 2001

2.      West, M. A. et al. Science 305: 1153-1157, 2004