Abstract
The type of adaptive immune response following host-fungi interaction is largely determined at the level of the antigen-presenting cells, and in particular by dendritic cells (DCs). The extent to which transcriptional regulatory events determine the decision making process in DCs is still an open question. By applying the highly structured DC-ATLAS pathways to analyze DC responses, we classified the various stimuli by revealing the modular nature of the different transcriptional programs governing the recognition of either pathogenic or commensal fungi. Through comparison of the network parts affected by DC stimulation with fungal cells and purified single agonists, we could determine the contribution of each receptor during the recognition process. We observed that initial recognition of a fungus creates a temporal window during which the simultaneous recruitment of cell surface receptors can intensify, complement and sustain the DC activation process. The breakdown of the response to whole live cells, through the purified components, showed how the response to invading fungi uses a set of specific modules. We find that at the start of fungal recognition, DCs rapidly initiate the activation process. Ligand recognition is further enhanced by over-expression of the receptor genes, with a significant correspondence between gene expression and protein levels and function. Then a marked decrease in the receptor levels follows, suggesting that at this moment the DC commits to a specific fate. Overall our pathway based studies show that the temporal window of the fungal recognition process depends on the availability of ligands and is different for pathogens and commensals. Modular analysis of receptor and signalling-adaptor expression changes, in the early phase of pathogen recognition, is a valuable tool for rapid and efficient dissection of the pathogen derived components that determine the phenotype of the DC and thereby the type of immune response initiated.
Highlights
In the past decade has it become clear that the innate immune system recognizes various classes of microorganisms, and initiates and modulates the subsequent adaptive responses carried out by T cells and B cells
For dendritic cells (DCs)-SIGN we defined (Figure S1) a modular structure composed of two receptor/sensing modules (‘‘s’’ modules), based on two known adaptors for DC-specific ICAM-3 grabbing nonintegrin (DC-SIGN) - LARG and LYN - resulting in two transduction modules (‘‘t’’) and three outcome modules (‘‘o’’)
In addition to the Dectin-1 pathways, our findings indicate that genes present in the outcome modules of DC-SIGN in general exert an important role in the recognition of entire fungal cells, consistent with what was previously reported at the protein level [25,26,27]
Summary
In the past decade has it become clear that the innate immune system recognizes various classes of microorganisms, and initiates and modulates the subsequent adaptive responses carried out by T cells and B cells. DCs contain a large array of pattern-recognition receptors (PRRs), which recognize conserved microbial components called pathogen-associated molecular patterns (PAMPs) and upon binding start a specific transcriptional program that activates the DC, directing the immune response suited to face the recognized pathogen. Engagement of different PRRs by the host immune surveillance results in complex signaling and determines subsequent fungal antigen processing and antigen presentation, contributing to the disparate patterns of reactivity observed locally in response to fungi [13,14]. Pathogens mask cell wall components to circumvent processing and presentation [15,16], and use C-type lectin receptors to escape immune activation
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