Dectin-1: unique appetite for yeast

Comment on Herre et al, page 4038

Dectin-1 is a myeloid receptor involved in phagocytosis of fungal pathogens that uses a unique mechanism of internalization and cellular signaling.

Phagocytosis of pathogens is a critically important activity of cells of the innate immune system. Professional phagocytes, such as macrophages, are equipped with a wide array of cell surface receptors, which are either directly or indirectly involved in recognition, uptake, and presentation of these antigens, as well as cellular signaling. The indirect receptors, such as Fcγ receptor (FcγR) and complement receptors, are well characterized and recognize pathogens opsonized with immunoglobulins and active complement fragments.¹  Signaling via FcγRis especially well established and involves the associated common gamma chain, which bears an immunoreceptor tyrosine-based activation motif (ITAM) critical for this activity. In addition, professional phagocytes/antigen-presenting cells express direct pattern recognition receptors, many belonging to the C-type lectin family, including macrophage mannose receptor (CD206) and scavenger receptor, but also receptors specific for dendritic cell subsets such as DC-SIGN (CD209), Langerin (CD207), DEC-205 (CD205), and BDCA2.²  Dectin-1 is another receptor broadly expressed on myeloid cells belonging to this family that recognizes β-glucan structures, such as those exposed on the outside of fungal pathogens.³  Interestingly, this receptor combines the extracellular lectin domain with an intracellular region reminiscent of an ITAM motif.

A study by Herre and colleagues in this issue of Blood further unravels the intracellular mechanisms of Dectin-1-mediated phagocytosis. Using transfected 3T3 fibroblasts, the critical contribution of the ITAM motif was demonstrated. Intracellular truncation or point mutation in the membrane proximal tyrosine residue did not affect binding, but hampered phagocytosis of yeast particles. The use of pharmacologic inhibitors also suggested that Dectin-1-mediated and FcγR-mediated signaling followed a similar process. However, major differences were found when studies were performed in either RAW macrophages, transduced with the Dectin-1 receptor, or freshly isolated macrophages. For FcγR signaling, the Syk kinase is a pivotal component,⁴  as confirmed by the authors showing the inability of macrophages from Syk^-/- mice to take up opsonized sheep red blood cells. However, the same cells were fully competent in Dectin-1-mediated internalization (see figure). Herre et al went one step further and investigated whether the intracellular trafficking of the Dectin-1 receptor was affected by the nature of the ligand. The uptake of large particles was associated with a re-expression of the receptor completely dependent of de novo protein synthesis. However, smaller β-glucans, such as laminarin, showed a receptor recycling independent of protein synthesis. It is conceivable that this difference has major implications for the antigen-presentation process and deserves further attention. Moreover it will be interesting to study these processes in the different myeloid cells expressing Dectin-1. Finally, the results of Herre et al raise the question of whether other cellular processes initiated by Dectin-1 triggering, such as production of inflammatory mediators, are also determined by the nature of the recognized ligand.