The Toll‐like receptor ligand MALP‐2 stimulates dendritic cell maturation and modulates proteasome composition and activity

Link, Claudia; Gavioli, Riccardo; Ebensen, Thomas; Canella, Alessandro; Reinhard, Elena; Guzmán, Carlos A.

doi:10.1002/eji.200324511

Cited by 57 publications

(48 citation statements)

References 43 publications

(38 reference statements)

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“…Our experiments with cytokine receptor knockout (KO) mice demonstrate that lack of TNF-␣ signaling does not influence the induction of I-proteasome during L. monocytogenes infection. Furthermore, it has been shown that stimulation of TLRs leads to induction of immunosubunits in dendritic cells (35) and is involved in the control of L. monocytogenes infection (36). However, our studies suggest that stimulation of TLR by bacterial components cannot induce I-proteasomes in nonlymphoid tissues.…”

Section: Discussioncontrasting

confidence: 54%

Immunoproteasomes Are Essential for Clearance ofListeria monocytogenesin Nonlymphoid Tissues but Not for Induction of Bacteria-Specific CD8+ T Cells

Strehl

Joeris

Rieger

et al. 2006

The Journal of Immunology

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Microbial infections induce the replacement of constitutive proteasomes by immunoproteasomes (I-proteasomes). I-proteasomes support efficient generation of MHC class I epitopes and influence immunodominance hierarchies of CD8+ T cells. Recently, the function of I-proteasomes in antimicrobial responses was challenged by showing that the lack of I-proteasomes has no effect on induction and function of lymphocytic choriomeningitis virus-specific CD8+ T cells. Here, we show that infection with Listeria monocytogenes rapidly induces I-proteasomes in nonlymphoid tissues, which leads to enhanced generation of protection relevant CD8+ T cell epitopes. I-proteasome-deficient mice (β5i−/− mice) exhibited normal frequencies of L. monocytogenes-specific CD8+ T cells. However, clearance of L. monocytogenes in liver but not spleen was significantly impaired in I-proteasome-deficient mice. In summary, our studies demonstrate that induction of I-proteasomes is required for CD8+ T cell-mediated elimination of L. monocytogenes from nonlymphoid but not lymphoid tissues.

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Section: Discussioncontrasting

confidence: 54%

Immunoproteasomes Are Essential for Clearance ofListeria monocytogenesin Nonlymphoid Tissues but Not for Induction of Bacteria-Specific CD8+ T Cells

Strehl

Joeris

Rieger

et al. 2006

The Journal of Immunology

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“…It is likely that this high immunogenicity arises from the covalently linked lipid moiety, which acts as a danger signal (1-3) by stimulating the innate immune system via the pattern recognition receptor TLR 2/6. This capacity is retained by both natural MALP-2 and synthetic derivatives, which are able to activate different cellular subtypes (12,19,23). However, the role played by these lipopeptides during natural infections has not been elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies revealed that MALP-2 is an agonist of the TLR2/6 heterodimer, leading to a Toll-IL-1R domain-containing adapter protein and MyD88-dependent activation of NF-B in macrophages (9 -11). Consequently, incubation of macrophages and dendritic cells with MALP-2 results in the secretion of proinflammatory cytokines and enhances the capacity of dendritic cells to present Ags to T cells (12). Since the adjuvanticity of MALP-2 is characterized by strong humoral responses and B cells express TLR2/6 (13), B cells could be a potential target for MALP-2-mediated activation in vivo.…”

mentioning

confidence: 99%

The Mucosal Adjuvant Macrophage-Activating Lipopeptide-2 Directly Stimulates B Lymphocytes via the TLR2 without the Need of Accessory Cells

Borsutzky

Kretschmer

Becker

et al. 2005

The Journal of Immunology

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The macrophage-activating lipopeptide-2 (MALP-2) is an agonist of the TLR heterodimer 2/6, which exhibits potent activity as mucosal adjuvant, promoting strong humoral and cellular responses. Although B cells expressing TLR2/6 are potential targets, very little is known about the effect of MALP-2 on B cells. Studies were performed using total spleen cells or purified B cells from WT mice or animals deficient in TLR2, T cells, B cells, or specific subpopulations of B cells. They demonstrated that MALP-2 promotes a T cell-independent activation and maturation of B cells (mainly follicular but also B-1a and marginal zone B cells) via TLR2. MALP-2 also increased the frequency of IgM- and IgG-secreting cells, but bystander cells were required for IgA secretion. Activated B cells exhibited increased expression of activation markers and ligands that are critical for cross-talk with T cells (CD19, CD25, CD80, CD86, MHC I, MHC II, and CD40). Immunization of mice lacking T cells showed that MALP-2-mediated stimulation of TLR2/6 was unable to circumvent the need of T cell help for efficient Ag-specific B cell activation. Immunization of mice lacking B cells demonstrated that B cells are critical for MALP-2-dependent improvement of T cell responses. The knowledge emerging from this work suggests that MALP-2-mediated activation of B cells through TLR2/6 is critical for adjuvanticity. B cell stimulation by pattern recognition receptors seems to be a basic mechanism that can be exploited to improve the immunogenicity of vaccine formulations.

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“…95 These results have been independently confirmed in BALB/c mice using MALP-2, and extended to show that the lipopeptide also upregulates immunoproteasome (LMP2, LMP7 and MECL1) activity in a dose-dependent manner, suggesting that lipopeptides may indirectly enhance MHC Class I-restricted responses by accelerated antigen processing and peptide presentation. 96 Importantly, the effects of lipopeptides on APC maturation and antigen presentation have also been demonstrated in human DCs. 97 MALP-2 directly stimulates murine B lymphocytes without accessory APC help in a TLR2-and dose-dependent fashion.…”

Section: Tlr1/tlr2/tlr6 Agonistic Bacterial Lipoteichoic Acid and Lipmentioning

confidence: 99%

Potential adjuvantic properties of innate immune stimuli

et al. 2009

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Just as the prescient comment by Gaston Ramon was relegated to the last footnote of his 1926 paper, 1 so has research on the mechanisms of action of adjuvants, until recently, languished as parenthetical annotations and addenda in the archives of immunology and vaccine development. Ramon defined immunological adjuvants as "substances used in combination with a specific antigen that produced a more robust immune response than the antigen alone." Interestingly enough, he was referring to his empirical findings that the addition of bread crumbs, tapioca, saponin and 'starch oil' to antigenic preparations greatly enhanced antibody responses to diphtheria or tetanus. 2 A year later, the adjuvanticity of aluminum salts (primarily phosphate and hydroxide) was discovered by Glenny and coworkers. 3 In the 83 years that have elapsed, the repertoire of investigational adjuvants has grown to encompass a very wide range of materials, 4 but aluminum salt-based mineral salts (generically, and incorrectly, termed "alum") have remained the only adjuvants currently approved by the FDA. Aluminum salts have enjoyed a good safety record, but they are weak adjuvants for antibody induction and induce a T helper-2 (T H 2)-skewed, rather than a T helper-1 (T H 1) response. 5,6 Furthermore, not only are aluminum salts ineffective at inducing cytotoxic T lymphocyte (CTL) or mucosal IgA antibody responses, but also have a propensity to induce IgE responses, which have been associated with allergic reactions in some subjects. 5,6 Very recent reports implicate the Nalp3 inflammasome, a component of the innate immune response, as the effector limb of alum-associated adjuvanticity. [7][8][9] In 1962, Dresser observed that injection of purified soluble proteins not only failed to stimulate an immune response, but tolerized animals unless a bacterial extract was admixed with the protein immunogen. 10 This led him to redefine adjuvanticity as "a property of a substance which can act as a physiological switch, directing at least some immunologically competent cells to respond by making antibody rather than by becoming immunologically paralyzed by the antigen," 11 confirming Johnson's earlier observations that lipopolysaccharide (LPS) from Gram-negative bacteria exerted potent adjuvant properties, 12 and perhaps paved the way for the subsequent discovery of the wide range of microorganism-derived adjuvants. 13 TLRs are pattern recognition receptors present on diverse cell types that recognize specific molecular patterns present in molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs). 14,15 There are 10 TLRs in the human genome;

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The Toll‐like receptor ligand MALP‐2 stimulates dendritic cell maturation and modulates proteasome composition and activity

Cited by 57 publications

References 43 publications

Immunoproteasomes Are Essential for Clearance ofListeria monocytogenesin Nonlymphoid Tissues but Not for Induction of Bacteria-Specific CD8+ T Cells

Immunoproteasomes Are Essential for Clearance ofListeria monocytogenesin Nonlymphoid Tissues but Not for Induction of Bacteria-Specific CD8+ T Cells

The Mucosal Adjuvant Macrophage-Activating Lipopeptide-2 Directly Stimulates B Lymphocytes via the TLR2 without the Need of Accessory Cells

Potential adjuvantic properties of innate immune stimuli

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