Targeted delivery of lipid antigen to macrophages via the CD169/sialoadhesin endocytic pathway induces robust invariant natural killer T cell activation

Kawasaki, Norihito; Vela, José Luis; Nycholat, Corwin M.; Rademacher, Christoph; Khurana, Archana; Rooijen, Nico van; Crocker, Paul R.; Kronenberg, Mitchell; Paulson, James C.

doi:10.1073/pnas.1219888110

Cited by 103 publications

(88 citation statements)

References 40 publications

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“…Therefore, a controlled delivery of a-GalCer is a requisite to optimize iNKT cell responses. A recent study showed that specific targeting of a-GalCer to CD169 + macrophages leads to an efficient iNKT cell activation in vivo but fails to trigger transactivation of innate immune cells (42). The consequence on the recall response was not reported in the later study.…”

Section: Nps Incorporating A-galcer and Ag Protect Against Tumor Devementioning

confidence: 85%

“…Of interest, and in contrast with specific targeting of a-GalCer to CD169 + macrophages (42), active delivery of a-GalCer to CD8a + DCs also increased the transactivation of NK, gd T lymphocytes, and DCs. Thus, CD8a + DCs targeting via DEC205 optimizes the iNKT cell-mediated innate immune response in agreement with the fact that CD8a + DCs are a dominant source of bioactive IL-12 (26,49).…”

Section: Nps Incorporating A-galcer and Ag Protect Against Tumor Devementioning

confidence: 94%

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Targeted Delivery of α-Galactosylceramide to CD8α+ Dendritic Cells Optimizes Type I NKT Cell–Based Antitumor Responses

Macho-Fernandez

Cruz

Ghinnagow

et al. 2014

The Journal of Immunology

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Immunotherapy aiming at enhancing innate and acquired host immunity is a promising approach for cancer treatment. The invariant NKT (iNKT) cell ligand α-galactosylceramide (α-GalCer) holds great promise in cancer therapy, although several concerns limit its use in clinics, including the uncontrolled response it promotes when delivered in a nonvectorized form. Therefore, development of delivery systems to in vivo target immune cells might be a valuable option to optimize iNKT cell–based antitumor responses. Using dendritic cell (DC)–depleted mice, DC transfer experiments, and in vivo active cell targeting, we show that presentation of α-GalCer by DCs not only triggers optimal primary iNKT cell stimulation, but also maintains secondary iNKT cell activation after challenge. Furthermore, targeted delivery of α-GalCer to CD8α+ DCs, by means of anti-DEC205 decorated nanoparticles, enhances iNKT cell–based transactivation of NK cells, DCs, and γδ T cells. We report that codelivery of α-GalCer and protein Ag to CD8α+ DCs triggers optimal Ag-specific Ab and cytotoxic CD8+ T cell responses. Finally, we show that targeting nanoparticles containing α-GalCer and Ag to CD8α+ DCs promotes potent antitumor responses, both in prophylactic and in therapeutic settings. Our data may have important implications in tumor immunotherapy and vaccine development.

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Section: Nps Incorporating A-galcer and Ag Protect Against Tumor Devementioning

confidence: 85%

Section: Nps Incorporating A-galcer and Ag Protect Against Tumor Devementioning

confidence: 94%

Targeted Delivery of α-Galactosylceramide to CD8α+ Dendritic Cells Optimizes Type I NKT Cell–Based Antitumor Responses

Macho-Fernandez

Cruz

Ghinnagow

et al. 2014

The Journal of Immunology

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“…Siglecs which lack an ITIM domain (such as Siglec-14, 15, and 16) associate with DAP12 via a positively charged amino acid in their transmembrane region to activate receptors through the recruitment of Syk (15,40). Siglec-1, the first discovered member of Siglecs, has been shown to play an important role in sialylated pathogen uptake (17,19,(53)(54)(55), antigen presentation (56,57), lymphocyte proliferation (58), self-tolerance (59,60) and antiviral immune response (47). However, the biological function of Siglec-1 in endotoxin tolerance is unknown.…”

Section: Discussionmentioning

confidence: 99%

Induction of Siglec-1 by Endotoxin Tolerance Suppresses the Innate Immune Response by Promoting TGF-β1 Production

Lan

Ren

et al. 2016

Journal of Biological Chemistry

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Sepsis is one of the leading causes of death worldwide. Although the prevailing theory for the sepsis syndrome is a condition of uncontrolled inflammation in response to infection, sepsis is increasingly being recognized as an immunosuppressive state known as endotoxin tolerance. We found sialylation of cell surface was significantly increased on LPS-induced tolerant cells; knockdown of Neu1 in macrophage cell line RAW 264.7 cells resulted in enhanced LPS-induced tolerance, whereas overexpression of Neu1 or treatment with sialidase abrogated LPS-induced tolerance, as defined by measuring TNF-␣ levels in the culture supernatants. We also found that the expression of Siglec-1 (a member of sialic acid-binding Ig (I)-like lectin family members, the predominant sialic acid-binding proteins on cell surface) was specifically up-regulated in endotoxin tolerant cells and the induction of Siglec-1 suppresses the innate immune response by promoting TGF-␤1 production. The enhanced TGF-␤1 production by Siglec-1 was significantly attenuated by spleen tyrosine kinase (Syk) inhibitor. Knockdown of siglec-1 in RAW 264.7 cells resulted in inhibiting the production of TGF-␤1 by ubiquitin-dependent degradation of Syk. Mechanistically, Siglec-1 associates with adaptor protein DNAX-activation protein of 12 kDa (DAP12) and transduces a signal to Syk to control the production of TGF-␤1 in endotoxin tolerance. Thus, Siglec-1 plays an important role in the development of endotoxin tolerance and targeted manipulation of this process could lead to a new therapeutic opportunity for patients with sepsis.Sepsis is generally defined as a systemic inflammatory response syndrome in response to infection. Sepsis can be potentially life threatening; of more than 1 million Americans who are diagnosed with severe sepsis every year, between 28 and 50% will die from this disease (1, 2). It is well-recognized that patients with sepsis are often immune suppressed, a state of reduced responsiveness to endotoxin known as endotoxin tolerance, deaths in this immunosuppressive phase are typically due to failure to control the secondary infections (3-5). The molecular mechanisms underlying this endotoxin tolerance phenomenon is poorly understood.Sialic acids are a family of nine-carbon acidic monosaccharides and are involved in immune response, such as host-pathogen recognition, migration, and antigen presentation. Mounting experimental evidence suggests that the presence of sialic acid residue act as a marker of self in the immune system, as such residues are absent from most microbes (6). Indeed, host cells can be lysed by immune cytotoxic effector mechanisms after extensive desialylation, an observation that demonstrates the significant role played by cell surface sialic acids in the selfrecognition process (7). In addition, normal human serum contains natural antibodies to sialidase-treated red blood cells (7-9), lymphocytes (10), and thymocytes (7). Recently, Meesmann et al. showed that desialylation acted as an "eat me" signal and caused an enhanced upt...

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“…Siglec1 has been shown to play an important role in the capture and internalization of pathogens via binding to sialic acid residues expressed on the surface of some important pathogens such as HIV-1 [12] and porcine reproductive and respiratory syndrome virus [13]. Siglec1 has also been shown to participate in antigen presentation and induction of adaptive immune responses [14,15]. However, the biological functions of Siglec1 in antiviral innate immunity remain elusive, and its cytosolic signaling pathway is still unknown.…”

Section: Introductionmentioning

confidence: 99%

Siglec1 suppresses antiviral innate immune response by inducing TBK1 degradation via the ubiquitin ligase TRIM27

et al. 2015

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Type I interferon (IFN) production plays pivotal roles in host antiviral innate immune responses, but an excessive production of type I IFN leads to the development of immunopathological conditions. Investigations on the regulatory mechanisms underlying host type I IFN production are currently of great interest. Here, we found that the expression of lectin family member Siglec1 was upregulated by viral infection in macrophages, which was dependent on the IFN/JAK/STAT1 signaling pathway. Siglec1 was found to negatively regulate viral infection-triggered type I IFN production. Mechanistically, Siglec1 associates with DAP12 to recruit and activate the scaffolding function of SHP2; SHP2 then recruits E3 ubiquitin ligase TRIM27, which induces TBK1 degradation via K48-linked ubiquitination at Lys251 and Lys372. Therefore, viral infection-induced upregulation of Siglec1 feedback loop inhibits type I IFN production and suppresses antiviral innate immune responses. Our study outlines a novel mechanism of negative regulation of type I IFN production, which may help virus to escape immune elimination.

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Targeted delivery of lipid antigen to macrophages via the CD169/sialoadhesin endocytic pathway induces robust invariant natural killer T cell activation

Cited by 103 publications

References 40 publications

Targeted Delivery of α-Galactosylceramide to CD8α+ Dendritic Cells Optimizes Type I NKT Cell–Based Antitumor Responses

Targeted Delivery of α-Galactosylceramide to CD8α+ Dendritic Cells Optimizes Type I NKT Cell–Based Antitumor Responses

Induction of Siglec-1 by Endotoxin Tolerance Suppresses the Innate Immune Response by Promoting TGF-β1 Production

Siglec1 suppresses antiviral innate immune response by inducing TBK1 degradation via the ubiquitin ligase TRIM27

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