Editors' ChoiceImmunology

No Receptor Necessary

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Science Signaling  19 Apr 2011:
Vol. 4, Issue 169, pp. ec109
DOI: 10.1126/scisignal.4169ec109

Aluminum salts (alum) act as adjuvants to enhance the efficacy of vaccines; however, the mechanisms whereby alum potentiates the immune response to antigen has been controversial (see Mbow et al.). Flach et al. used atomic force microscopy to investigate interactions between alum crystals and dendritic cells (DCs, a class of cells that process antigen for presentation to T cells) and observed an oscillatory binding pattern indicative of abortive phagocytosis. Electron microscopic analysis corroborated the lack of alum internalization. Alum bound DCs that had been treated with a proteolytic enzyme, suggesting that it associated with membrane lipids rather than cell surface proteins, and analyses of its interactions with fluorescently labeled lipids, monolayers of individual lipids, or bilayers of defined composition implicated sphingomyelin and cholesterol in the interaction. Methyl-β-cyclodextrin, which depletes membrane cholesterol, blocked alum binding, and pharmacological analysis, combined with investigation of DCs lacking various proteins, implicated ITAM (immunoreceptor tyrosine-based activation motif)–containing receptors and the downstream mediators Syk (spleen tyrosine kinase) and phosphatidylinositol 3-kinase in DC-alum binding. Syk can stimulate the activation of extracellular signal–regulated kinase (ERK), and alum treatment of DCs led to an increase in ERK phosphorylation after a 5- to 10-minute delay. Macrophages, another class of antigen-presenting cells, had little affinity for alum and showed constant or immediate ERK phosphorylation; intriguingly, pharmacological activation of ERK attenuated DC binding to alum, whereas ERK inhibition promoted its binding by macrophages. Alum facilitated antigen uptake by DCs, promoted migration of antigen-exposed DCs to lymph nodes in mice, and antigen-independently increased DC surface abundance of intercellular adhesion molecule–1 (ICAM-1), enabling tight interactions between DCs and CD4+ T cells (through ICAM-1 and its binding partner LFA-1). The authors propose that alum binding to DC membrane lipids promotes the aggregation of cholesterol-rich regions (and thus ITAM-containing receptor clustering), thereby activating signaling pathways that promote DC-CD4+ T cell interactions.

T. L. Flach, G. Ng, A. Hari, M. D. Desrosiers, P. Zhang, S. M. Ward, M. E. Seamone, A. Vilaysane, A. D. Mucsi, Y. Fong, E. Prenner, C. C. Ling, J. Tschopp, D. A. Muruve, M. W. Amrein, Y. Shi, Alum interaction with dendritic cell membrane lipids is essential for its adjuvanticity. Nat. Med. 17, 479–487 (2011). [PubMed]

M. L. Mbow, E. De Gregorio, J. B. Ulmer, Alum’s adjuvant action: Grease is the word. Nat. Med. 17, 415–416 (2011). [PubMed]

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