Detection of β-glucans in fungal cell walls by the pattern recognition receptor Dectin-1 on phagocytic cells elicits phosphorylation and activation of tyrosine kinases of the Src family, such as Syk. Signaling pathways downstream of Src tyrosine kinases trigger antimicrobial responses [such as phagocytosis and production of reactive oxygen species (ROS)], as well as inflammatory responses [such as production of cytokines, including tumor necrosis factor–α (TNF-α) and interleukin-6 (IL-6)]. Other pattern recognition receptors, such as Toll-like receptors, initiate innate immune responses when activated by soluble microbial stimuli. However, antifungal responses mediated by Dectin-1 are useful only when cells are in direct contact with microbes, leading Goodridge et al. to explore how Dectin-1 recognizes its ligand. Dectin-1–dependent responses in macrophages, dendritic cells, and neutrophils were initiated by whole glucan particles or immobilized β-glucan (to mimic presentation on a yeast cell) but not soluble β-glucan (although soluble β-glucan bound to Dectin-1 on cells). These responses included activation of Syk, phagocytosis, and production of TNF-α, IL-6, and ROS. Initial activation of Dectin-1 in macrophages required the membrane tyrosine phosphatases CD45 and CD148. In T cells, CD45 must be removed from the T cell receptor to enable productive signaling. Similarly, in primary macrophages and a macrophage cell line, CD45 and CD148 were excluded from the contact site of the β-glucan particle, where clustered Dectin-1 and active Syk were detected. Thus, the selective response of Dectin-1 to the particulate form of its ligand ensures that antifungal responses are triggered only when phagocytic cells directly contact fungal cells. The authors propose the concept of “phagocytic synapses,” which are analogous to the immune synapses between T cells and dendritic cells.
H. S. Goodridge, C. N. Reyes, C. A. Becker, T. R. Katsumoto, J. Ma, A. J. Wolf, N. Bose, A. S. H. Chan, A. S. Magee, M. E. Danielson, A. Weiss, J. P. Vasilakos, D. M. Underhill, Activation of the innate immune receptor Dectin-1 upon formation of a ‘phagocytic synapse.’ Nature 472, 471–475 (2011). [PubMed]