Adjuvanticity of a synthetic cord factor analogue for subunit Mycobacterium tuberculosis vaccination requires FcRγ–Syk–Card9-dependent innate immune activation

Kerstin Werninghaus, Anna Babiak, Olaf Gross, Christoph Hölscher, Harald Dietrich, Else Marie Agger, Jörg Mages, Attila Mocsai, Hanne Schoenen, Katrin Finger, Falk Nimmerjahn, Gordon D Brown, Carsten Kirschning, Antje Heit, Peter Andersen, Hermann Wagner, Jürgen Ruland, Roland Lang

Research output: Contribution to journalArticle

199 Citations (Scopus)

Abstract

Novel vaccination strategies against Mycobacterium tuberculosis (MTB) are urgently needed. The use of recombinant MTB antigens as subunit vaccines is a promising approach, but requires adjuvants that activate antigen-presenting cells (APCs) for elicitation of protective immunity. The mycobacterial cord factor Trehalose-6,6-dimycolate (TDM) and its synthetic analogue Trehalose-6,6-dibehenate (TDB) are effective adjuvants in combination with MTB subunit vaccine candidates in mice. However, it is unknown which signaling pathways they engage in APCs and how these pathways are coupled to the adaptive immune response. Here, we demonstrate that these glycolipids activate macrophages and dendritic cells (DCs) via Syk-Card9-Bcl10-Malt1 signaling to induce a specific innate activation program distinct from the response to Toll-like receptor (TLR) ligands. APC activation by TDB and TDM was independent of the C-type lectin receptor Dectin-1, but required the immunoreceptor tyrosine-based activation motif-bearing adaptor protein Fc receptor gamma chain (FcRgamma). In vivo, TDB and TDM adjuvant activity induced robust combined T helper (Th)-1 and Th-17 T cell responses to a MTB subunit vaccine and partial protection against MTB challenge in a Card9-dependent manner. These data provide a molecular basis for the immunostimulatory activity of TDB and TDM and identify the Syk-Card9 pathway as a rational target for vaccine development against tuberculosis.
Original languageEnglish
Pages (from-to)89-97
Number of pages9
JournalJournal of Experimental Medicine
Volume206
Issue number1
DOIs
Publication statusPublished - 16 Jan 2009

Fingerprint

Cord Factors
Trehalose
Mycobacterium tuberculosis
Vaccination
Subunit Vaccines
Antigen-Presenting Cells
Tuberculosis Vaccines
Immunoreceptor Tyrosine-Based Activation Motif
C-Type Lectins
IgG Receptors
Th17 Cells
Toll-Like Receptors
Glycolipids
Adaptive Immunity
Dendritic Cells
Immunity
Tuberculosis
Vaccines
Macrophages
Ligands

Keywords

  • adaptor proteins, signal transducing
  • adjuvants, immunologic
  • animals
  • CD4-positive T-lymphocytes
  • caspases
  • cytokines
  • dendritic cells
  • glycolipids
  • immunity, innate
  • immunoglobulin G
  • intracellular signaling peptides and proteins
  • lung
  • lymph nodes
  • macrophage activation
  • macrophages
  • mice
  • mice, inbred C57BL
  • mice, knockout
  • neoplasm proteins
  • protein-tyrosine kinases
  • receptors, IgE
  • signal transduction
  • t-lymphocytes, helper-inducer
  • tuberculosis vaccines
  • tuberculosis, pulmonary
  • vaccines, subunit

Cite this

Adjuvanticity of a synthetic cord factor analogue for subunit Mycobacterium tuberculosis vaccination requires FcRγ–Syk–Card9-dependent innate immune activation. / Werninghaus, Kerstin; Babiak, Anna; Gross, Olaf; Hölscher, Christoph; Dietrich, Harald; Agger, Else Marie; Mages, Jörg; Mocsai, Attila; Schoenen, Hanne; Finger, Katrin; Nimmerjahn, Falk; Brown, Gordon D; Kirschning, Carsten; Heit, Antje; Andersen, Peter; Wagner, Hermann; Ruland, Jürgen; Lang, Roland.

In: Journal of Experimental Medicine, Vol. 206, No. 1, 16.01.2009, p. 89-97.

Research output: Contribution to journalArticle

Werninghaus, K, Babiak, A, Gross, O, Hölscher, C, Dietrich, H, Agger, EM, Mages, J, Mocsai, A, Schoenen, H, Finger, K, Nimmerjahn, F, Brown, GD, Kirschning, C, Heit, A, Andersen, P, Wagner, H, Ruland, J & Lang, R 2009, 'Adjuvanticity of a synthetic cord factor analogue for subunit Mycobacterium tuberculosis vaccination requires FcRγ–Syk–Card9-dependent innate immune activation', Journal of Experimental Medicine, vol. 206, no. 1, pp. 89-97. https://doi.org/10.1084/jem.20081445
Werninghaus, Kerstin ; Babiak, Anna ; Gross, Olaf ; Hölscher, Christoph ; Dietrich, Harald ; Agger, Else Marie ; Mages, Jörg ; Mocsai, Attila ; Schoenen, Hanne ; Finger, Katrin ; Nimmerjahn, Falk ; Brown, Gordon D ; Kirschning, Carsten ; Heit, Antje ; Andersen, Peter ; Wagner, Hermann ; Ruland, Jürgen ; Lang, Roland. / Adjuvanticity of a synthetic cord factor analogue for subunit Mycobacterium tuberculosis vaccination requires FcRγ–Syk–Card9-dependent innate immune activation. In: Journal of Experimental Medicine. 2009 ; Vol. 206, No. 1. pp. 89-97.
@article{8fbaa75ae65740fa9575e52c6f719b66,
title = "Adjuvanticity of a synthetic cord factor analogue for subunit Mycobacterium tuberculosis vaccination requires FcRγ–Syk–Card9-dependent innate immune activation",
abstract = "Novel vaccination strategies against Mycobacterium tuberculosis (MTB) are urgently needed. The use of recombinant MTB antigens as subunit vaccines is a promising approach, but requires adjuvants that activate antigen-presenting cells (APCs) for elicitation of protective immunity. The mycobacterial cord factor Trehalose-6,6-dimycolate (TDM) and its synthetic analogue Trehalose-6,6-dibehenate (TDB) are effective adjuvants in combination with MTB subunit vaccine candidates in mice. However, it is unknown which signaling pathways they engage in APCs and how these pathways are coupled to the adaptive immune response. Here, we demonstrate that these glycolipids activate macrophages and dendritic cells (DCs) via Syk-Card9-Bcl10-Malt1 signaling to induce a specific innate activation program distinct from the response to Toll-like receptor (TLR) ligands. APC activation by TDB and TDM was independent of the C-type lectin receptor Dectin-1, but required the immunoreceptor tyrosine-based activation motif-bearing adaptor protein Fc receptor gamma chain (FcRgamma). In vivo, TDB and TDM adjuvant activity induced robust combined T helper (Th)-1 and Th-17 T cell responses to a MTB subunit vaccine and partial protection against MTB challenge in a Card9-dependent manner. These data provide a molecular basis for the immunostimulatory activity of TDB and TDM and identify the Syk-Card9 pathway as a rational target for vaccine development against tuberculosis.",
keywords = "adaptor proteins, signal transducing, adjuvants, immunologic, animals, CD4-positive T-lymphocytes, caspases, cytokines, dendritic cells, glycolipids, immunity, innate, immunoglobulin G, intracellular signaling peptides and proteins, lung, lymph nodes, macrophage activation, macrophages, mice, mice, inbred C57BL, mice, knockout, neoplasm proteins, protein-tyrosine kinases, receptors, IgE, signal transduction, t-lymphocytes, helper-inducer, tuberculosis vaccines, tuberculosis, pulmonary, vaccines, subunit",
author = "Kerstin Werninghaus and Anna Babiak and Olaf Gross and Christoph H{\"o}lscher and Harald Dietrich and Agger, {Else Marie} and J{\"o}rg Mages and Attila Mocsai and Hanne Schoenen and Katrin Finger and Falk Nimmerjahn and Brown, {Gordon D} and Carsten Kirschning and Antje Heit and Peter Andersen and Hermann Wagner and J{\"u}rgen Ruland and Roland Lang",
year = "2009",
month = "1",
day = "16",
doi = "10.1084/jem.20081445",
language = "English",
volume = "206",
pages = "89--97",
journal = "Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "Rockefeller University Press",
number = "1",

}

TY - JOUR

T1 - Adjuvanticity of a synthetic cord factor analogue for subunit Mycobacterium tuberculosis vaccination requires FcRγ–Syk–Card9-dependent innate immune activation

AU - Werninghaus, Kerstin

AU - Babiak, Anna

AU - Gross, Olaf

AU - Hölscher, Christoph

AU - Dietrich, Harald

AU - Agger, Else Marie

AU - Mages, Jörg

AU - Mocsai, Attila

AU - Schoenen, Hanne

AU - Finger, Katrin

AU - Nimmerjahn, Falk

AU - Brown, Gordon D

AU - Kirschning, Carsten

AU - Heit, Antje

AU - Andersen, Peter

AU - Wagner, Hermann

AU - Ruland, Jürgen

AU - Lang, Roland

PY - 2009/1/16

Y1 - 2009/1/16

N2 - Novel vaccination strategies against Mycobacterium tuberculosis (MTB) are urgently needed. The use of recombinant MTB antigens as subunit vaccines is a promising approach, but requires adjuvants that activate antigen-presenting cells (APCs) for elicitation of protective immunity. The mycobacterial cord factor Trehalose-6,6-dimycolate (TDM) and its synthetic analogue Trehalose-6,6-dibehenate (TDB) are effective adjuvants in combination with MTB subunit vaccine candidates in mice. However, it is unknown which signaling pathways they engage in APCs and how these pathways are coupled to the adaptive immune response. Here, we demonstrate that these glycolipids activate macrophages and dendritic cells (DCs) via Syk-Card9-Bcl10-Malt1 signaling to induce a specific innate activation program distinct from the response to Toll-like receptor (TLR) ligands. APC activation by TDB and TDM was independent of the C-type lectin receptor Dectin-1, but required the immunoreceptor tyrosine-based activation motif-bearing adaptor protein Fc receptor gamma chain (FcRgamma). In vivo, TDB and TDM adjuvant activity induced robust combined T helper (Th)-1 and Th-17 T cell responses to a MTB subunit vaccine and partial protection against MTB challenge in a Card9-dependent manner. These data provide a molecular basis for the immunostimulatory activity of TDB and TDM and identify the Syk-Card9 pathway as a rational target for vaccine development against tuberculosis.

AB - Novel vaccination strategies against Mycobacterium tuberculosis (MTB) are urgently needed. The use of recombinant MTB antigens as subunit vaccines is a promising approach, but requires adjuvants that activate antigen-presenting cells (APCs) for elicitation of protective immunity. The mycobacterial cord factor Trehalose-6,6-dimycolate (TDM) and its synthetic analogue Trehalose-6,6-dibehenate (TDB) are effective adjuvants in combination with MTB subunit vaccine candidates in mice. However, it is unknown which signaling pathways they engage in APCs and how these pathways are coupled to the adaptive immune response. Here, we demonstrate that these glycolipids activate macrophages and dendritic cells (DCs) via Syk-Card9-Bcl10-Malt1 signaling to induce a specific innate activation program distinct from the response to Toll-like receptor (TLR) ligands. APC activation by TDB and TDM was independent of the C-type lectin receptor Dectin-1, but required the immunoreceptor tyrosine-based activation motif-bearing adaptor protein Fc receptor gamma chain (FcRgamma). In vivo, TDB and TDM adjuvant activity induced robust combined T helper (Th)-1 and Th-17 T cell responses to a MTB subunit vaccine and partial protection against MTB challenge in a Card9-dependent manner. These data provide a molecular basis for the immunostimulatory activity of TDB and TDM and identify the Syk-Card9 pathway as a rational target for vaccine development against tuberculosis.

KW - adaptor proteins, signal transducing

KW - adjuvants, immunologic

KW - animals

KW - CD4-positive T-lymphocytes

KW - caspases

KW - cytokines

KW - dendritic cells

KW - glycolipids

KW - immunity, innate

KW - immunoglobulin G

KW - intracellular signaling peptides and proteins

KW - lung

KW - lymph nodes

KW - macrophage activation

KW - macrophages

KW - mice

KW - mice, inbred C57BL

KW - mice, knockout

KW - neoplasm proteins

KW - protein-tyrosine kinases

KW - receptors, IgE

KW - signal transduction

KW - t-lymphocytes, helper-inducer

KW - tuberculosis vaccines

KW - tuberculosis, pulmonary

KW - vaccines, subunit

U2 - 10.1084/jem.20081445

DO - 10.1084/jem.20081445

M3 - Article

VL - 206

SP - 89

EP - 97

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

IS - 1

ER -