Alum interaction with dendritic cell membrane lipids is essential for its adjuvanticity

Tracy L. Flach; Gilbert Ng; Aswin Hari; Melanie D. Desrosiers; Ping Zhang; Sandra M. Ward; Mark E. Seamone; Akosua Vilaysane; Ashley D. Mucsi; Yin Fong; Elmar Prenner; Chang Chun Ling; Jurg Tschopp; Daniel A. Muruve; Matthias W. Amrein; Yan Shi

doi:10.1038/nm.2306

Alum interaction with dendritic cell membrane lipids is essential for its adjuvanticity

Tracy L. Flach, Gilbert Ng, Aswin Hari, Melanie D. Desrosiers, Ping Zhang, Sandra M. Ward, Mark E. Seamone, Akosua Vilaysane, Ashley D. Mucsi, Yin Fong, Elmar Prenner, Chang Chun Ling, Jurg Tschopp, Daniel A. Muruve, Matthias W. Amrein, Yan Shi

Research output: Contribution to journal › Article › peer-review

340 Citations (Scopus)

Abstract

As an approved vaccine adjuvant for use in humans, alum has vast health implications, but, as it is a crystal, questions remain regarding its mechanism. Furthermore, little is known about the target cells, receptors, and signaling pathways engaged by alum. Here we report that, independent of inflammasome and membrane proteins, alum binds dendritic cell (DC) plasma membrane lipids with substantial force. Subsequent lipid sorting activates an abortive phagocytic response that leads to antigen uptake. Such activated DCs, without further association with alum, show high affinity and stable binding with CD4 ⁺T cells via the adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-1 (LFA-1). We propose that alum triggers DC responses by altering membrane lipid structures. This study therefore suggests an unexpected mechanism for how this crystalline structure interacts with the immune system and how the DC plasma membrane may behave as a general sensor for solid structures.

Original language	English
Pages (from-to)	479-487
Number of pages	9
Journal	Nature Medicine
Volume	17
Issue number	4
DOIs	https://doi.org/10.1038/nm.2306
Publication status	Published - Apr 2011
Externally published	Yes

Bibliographical note

Funding Information:
We thank L. Lanier and C. Lowell (University of California–San Francisco) for providing mouse bone marrows; P. Kubes (University of Calgary) for ICAM-1–, LFA-1– and TLR4-knockout mice; K. Rock (University of Massachusetts Medical School), P. Cresswell (Yale University), G. Dranoff (Harvard Medical School) and R. Yates and J. Deans (University of Calgary) for cell lines, L.J. Shen, M. Ho, Y. Yang and P. Santamaria for manuscript review; C. Olson and T. Fung for statistical software and advice; E. Chau for manuscript editing; F. Oskouie for cell culture assistance; and M. Schoel and W.-D. Xiang for SEM and transmission electron microscopy technical assistance. This work was supported by grants from the US National Institutes of Health to Y.S. and equipment donation from JPK instruments to M.W.A.

ASJC Scopus Subject Areas

General Biochemistry,Genetics and Molecular Biology

PubMed: MeSH publication types

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/nm.2306

Cite this

Flach, T. L., Ng, G., Hari, A., Desrosiers, M. D., Zhang, P., Ward, S. M., Seamone, M. E., Vilaysane, A., Mucsi, A. D., Fong, Y., Prenner, E., Ling, C. C., Tschopp, J., Muruve, D. A., Amrein, M. W., & Shi, Y. (2011). Alum interaction with dendritic cell membrane lipids is essential for its adjuvanticity. Nature Medicine, 17(4), 479-487. https://doi.org/10.1038/nm.2306

@article{69e8b8b219304942b1bef4c5f1e0cb1a,

title = "Alum interaction with dendritic cell membrane lipids is essential for its adjuvanticity",

abstract = "As an approved vaccine adjuvant for use in humans, alum has vast health implications, but, as it is a crystal, questions remain regarding its mechanism. Furthermore, little is known about the target cells, receptors, and signaling pathways engaged by alum. Here we report that, independent of inflammasome and membrane proteins, alum binds dendritic cell (DC) plasma membrane lipids with substantial force. Subsequent lipid sorting activates an abortive phagocytic response that leads to antigen uptake. Such activated DCs, without further association with alum, show high affinity and stable binding with CD4 +T cells via the adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-1 (LFA-1). We propose that alum triggers DC responses by altering membrane lipid structures. This study therefore suggests an unexpected mechanism for how this crystalline structure interacts with the immune system and how the DC plasma membrane may behave as a general sensor for solid structures.",

author = "Flach, {Tracy L.} and Gilbert Ng and Aswin Hari and Desrosiers, {Melanie D.} and Ping Zhang and Ward, {Sandra M.} and Seamone, {Mark E.} and Akosua Vilaysane and Mucsi, {Ashley D.} and Yin Fong and Elmar Prenner and Ling, {Chang Chun} and Jurg Tschopp and Muruve, {Daniel A.} and Amrein, {Matthias W.} and Yan Shi",

note = "Funding Information: We thank L. Lanier and C. Lowell (University of California–San Francisco) for providing mouse bone marrows; P. Kubes (University of Calgary) for ICAM-1–, LFA-1– and TLR4-knockout mice; K. Rock (University of Massachusetts Medical School), P. Cresswell (Yale University), G. Dranoff (Harvard Medical School) and R. Yates and J. Deans (University of Calgary) for cell lines, L.J. Shen, M. Ho, Y. Yang and P. Santamaria for manuscript review; C. Olson and T. Fung for statistical software and advice; E. Chau for manuscript editing; F. Oskouie for cell culture assistance; and M. Schoel and W.-D. Xiang for SEM and transmission electron microscopy technical assistance. This work was supported by grants from the US National Institutes of Health to Y.S. and equipment donation from JPK instruments to M.W.A.",

year = "2011",

month = apr,

doi = "10.1038/nm.2306",

language = "English",

volume = "17",

pages = "479--487",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Publishing Group",

number = "4",

}

TY - JOUR

T1 - Alum interaction with dendritic cell membrane lipids is essential for its adjuvanticity

AU - Flach, Tracy L.

AU - Ng, Gilbert

AU - Hari, Aswin

AU - Desrosiers, Melanie D.

AU - Zhang, Ping

AU - Ward, Sandra M.

AU - Seamone, Mark E.

AU - Vilaysane, Akosua

AU - Mucsi, Ashley D.

AU - Fong, Yin

AU - Prenner, Elmar

AU - Ling, Chang Chun

AU - Tschopp, Jurg

AU - Muruve, Daniel A.

AU - Amrein, Matthias W.

AU - Shi, Yan

N1 - Funding Information: We thank L. Lanier and C. Lowell (University of California–San Francisco) for providing mouse bone marrows; P. Kubes (University of Calgary) for ICAM-1–, LFA-1– and TLR4-knockout mice; K. Rock (University of Massachusetts Medical School), P. Cresswell (Yale University), G. Dranoff (Harvard Medical School) and R. Yates and J. Deans (University of Calgary) for cell lines, L.J. Shen, M. Ho, Y. Yang and P. Santamaria for manuscript review; C. Olson and T. Fung for statistical software and advice; E. Chau for manuscript editing; F. Oskouie for cell culture assistance; and M. Schoel and W.-D. Xiang for SEM and transmission electron microscopy technical assistance. This work was supported by grants from the US National Institutes of Health to Y.S. and equipment donation from JPK instruments to M.W.A.

PY - 2011/4

Y1 - 2011/4

N2 - As an approved vaccine adjuvant for use in humans, alum has vast health implications, but, as it is a crystal, questions remain regarding its mechanism. Furthermore, little is known about the target cells, receptors, and signaling pathways engaged by alum. Here we report that, independent of inflammasome and membrane proteins, alum binds dendritic cell (DC) plasma membrane lipids with substantial force. Subsequent lipid sorting activates an abortive phagocytic response that leads to antigen uptake. Such activated DCs, without further association with alum, show high affinity and stable binding with CD4 +T cells via the adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-1 (LFA-1). We propose that alum triggers DC responses by altering membrane lipid structures. This study therefore suggests an unexpected mechanism for how this crystalline structure interacts with the immune system and how the DC plasma membrane may behave as a general sensor for solid structures.

AB - As an approved vaccine adjuvant for use in humans, alum has vast health implications, but, as it is a crystal, questions remain regarding its mechanism. Furthermore, little is known about the target cells, receptors, and signaling pathways engaged by alum. Here we report that, independent of inflammasome and membrane proteins, alum binds dendritic cell (DC) plasma membrane lipids with substantial force. Subsequent lipid sorting activates an abortive phagocytic response that leads to antigen uptake. Such activated DCs, without further association with alum, show high affinity and stable binding with CD4 +T cells via the adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-1 (LFA-1). We propose that alum triggers DC responses by altering membrane lipid structures. This study therefore suggests an unexpected mechanism for how this crystalline structure interacts with the immune system and how the DC plasma membrane may behave as a general sensor for solid structures.

UR - http://www.scopus.com/inward/record.url?scp=79953747554&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79953747554&partnerID=8YFLogxK

U2 - 10.1038/nm.2306

DO - 10.1038/nm.2306

M3 - Article

C2 - 21399646

AN - SCOPUS:79953747554

SN - 1078-8956

VL - 17

SP - 479

EP - 487

JO - Nature Medicine

JF - Nature Medicine

IS - 4

ER -

Alum interaction with dendritic cell membrane lipids is essential for its adjuvanticity

Abstract

Bibliographical note

ASJC Scopus Subject Areas

PubMed: MeSH publication types

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this