Carbohydrate-specific signaling through the DC-SIGN signalosome tailors immunity to Mycobacterium tuberculosis, HIV-1 and Helicobacter pylori

Gringhuis S. I., et al. Nat Immunl. 10:1081-8 (2009).

Speaker : Chia-Ming Liu (劉佳明)                        Time: 15:10~16:00, Mar.10, 2010

Commentator: Dr. Yea-Lih Lin(林雅俐博士)       Place: Room 601

Abstract:

Dendritic cells (DCs) are instrumental in the development of pathogen-specific immune responses. The DC response is modulated depending on the repertoire of pathogen-recognition receptors (PRRs), including Toll-like receptors (TLRs) and C-type lectins. Trigger of several PRRs can induce diverse innate immune responses and the cooperation between different signaling pathways dictates the overall adaptive immune response. Recent studies have identified C-type lectins such as DC-SIGN as an important family of PRRs that are involved in the induction of specific gene expression to specific pathogens to modulate TLR signaling.¹ But the mechanisms behind these pathogen-specific effects of DC-SIGN signaling are unclear. In this paper, the DC-SIGN signaling pathway induced by mannose and fucose-expressing pathogen has been studied and found to be distinct. Binding of mannose-expressing pathogen such as Mycobacterium tuberculosis and human immunodeficiency virus type 1 (HIV-1) to DC-CIGN enhanced expression of IL-10, IL-12, and IL-6, whereas binding of fucose-expression pathogen such as Helicobacter pylori to DC-SIGN enhanced expression of IL-10, but downregulation of IL-12 and IL-6. Raf-1 activation by phosphorylation at Ser338 and Tyr340-341 was central to mannose dependent but not fucose dependent DC-SIGN mediated modulation of TLR4-induced cytokine production. The activation of Raf-1 by ManLAM required a signalosome consisting of LSP1 and the KSR-CNK-Raf-1 triad complex, which was constitutively bound to DC-SIGN in unstimulated DCs. The binding of DC-SIGN by ManLAM leaded to recruit upstream effectors of Raf-1 LARG and RhoA to the DC-SIGN signalsome and phosphorylated Raf-1. The phosphorylation of Ser338 involves LARG dependent activation of RhoA whereas Tyr340-341 phophorylation depend on a LARG induced but RhoA independent mechanism. On the other hand, fucose specific DC-SIGN trigger dissociated KSR-CNK-Raf-1 triad complex form the DC-SIGN signalosome that is LSP-1 dependent but Raf-1 independent. Thus, the distinct carbohydrates expressed on pathogen regulated the composition of the DC-SIGN signalosome and influenced the modulation of TLR4-induced cytokine responses.

References:

1.          Geijtenbeek T. B. H., et al. Signalling through C-type lectin receptors: shaping immune responses. Nat Rev Immunol. 29:465-79 (2009).