Signaling through NOD-2 and TLR-4 Bolsters the T cell Priming Capability of Dendritic cells by Inducing Autophagy

Khan, Nargis; Vidyarthi, Aurobind; Pahari, Susanta; Negi, Shikha; Aqdas, Mohammad; Nadeem, Sajid; Agnihotri, Tapan; Agrewala, Javed N.

doi:10.1038/srep19084

Cited by 41 publications

(31 citation statements)

References 34 publications

(38 reference statements)

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“…It might be possible that endogenous Gal-8 could exert additional effects, not totally recapitulated with the exogenous protein. In support, it was previously reported a key role for intracellular Gal-8 in the selective autophagy [5], a mechanism that has been associated with DC capability of T cell priming [43]. Notably, IL-6 secretion was also impaired in Lgals8 2/2 iBMDC; however, no significant differences were registered between Lgals8 2/2 and wt DC after activation with LPS, probably as a result of a compensation effect (Fig.…”

Section: Discussionsupporting

confidence: 81%

Galectin-8 activates dendritic cells and stimulates antigen-specific immune response elicitation

Carabelli

Quattrocchi²,

D'antuono

et al. 2017

Journal of Leukocyte Biology

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Galectin-8 (Gal-8) is a mammalian β-galactoside-binding lectin, endowed with proinflammatory properties. Given its capacity to enhance antigen-specific immune responses in vivo, we investigated whether Gal-8 was also able to promote APC activation to sustain T cell activation after priming. Both endogenous [dendritic cells (DCs)] and bone marrow-derived DCs (BMDCs) treated with exogenous Gal-8 exhibited a mature phenotype characterized by increased MHC class II (MHCII), CD80, and CD86 surface expression. Moreover, Gal-8-treated BMDCs (Gal-8-BMDCs) stimulated antigen-specific T cells more efficiently than immature BMDCs (iBMDCs). Proinflammatory cytokines IL-3, IL-2, IL-6, TNF, MCP-1, and MCP-5, as well as growth factor G-CSF, were augmented in Gal-8-BMDC conditioned media, with IL-6 as the most prominent. Remarkably, BMDCs from Gal-8-deficient mice ( BMDC) displayed reduced CD86 and IL-6 expression and an impaired ability to promote antigen-specific CD4 T cell activation. To test if Gal-8-induced activation correlates with the elicitation of an effective immune response, soluble Gal-8 was coadministrated with antigen during immunization of BALB/cJ mice in the experimental foot-and-mouth disease virus (FMDV) model. When a single dose of Gal-8 was added to the antigen formulation, an increased specific and neutralizing humoral response was developed, sufficient to enhance animal protection upon viral challenge. IL-6 and IFN-γ, as well as lymphoproliferative responses, were also incremented in Gal-8/antigen-immunized animals only at 48 h after immunization, suggesting that Gal-8 induces the elicitation of an inflammatory response at an early stage. Taking together, these findings argue in favor of the use of Gal-8 as an immune-stimulator molecule to enhance the adaptive immune response.

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Section: Discussionsupporting

confidence: 81%

Galectin-8 activates dendritic cells and stimulates antigen-specific immune response elicitation

Carabelli

Quattrocchi²,

D'antuono

et al. 2017

Journal of Leukocyte Biology

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“…This weakening can likely be attributed to an alteration in the pool of immunogenic peptides presented in MHC, which has been best determined in the context of so‐called cross‐presentation in DCs. Cross‐presentation is a process which enables the loading of MHC‐I on DCs with extracellular antigens, which is important for activation of, eg, CTL responses in melanoma . DCs with cross‐presentation capacity are characterized by increased levels of autophagy compared with DCs that do not cross‐present, with inhibition of autophagy reducing MHC‐I‐mediated cross‐presentation of ovalbumin (OVA) and human cytomegalovirus (CMV) peptides .…”

Section: Part Ii: the Role Of Autophagy In The Tumor Microenvironmentmentioning

confidence: 99%

The multifaceted role of autophagy in cancer and the microenvironment

Folkerts

Hilgendorf

Vellenga

et al. 2018

Medicinal Research Reviews

160

143

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Autophagy is a crucial recycling process that is increasingly being recognized as an important factor in cancer initiation, cancer (stem) cell maintenance as well as the development of resistance to cancer therapy in both solid and hematological malignancies. Furthermore, it is being recognized that autophagy also plays a crucial and sometimes opposing role in the complex cancer microenvironment. For instance, autophagy in stromal cells such as fibroblasts contributes to tumorigenesis by generating and supplying nutrients to cancerous cells. Reversely, autophagy in immune cells appears to contribute to tumor‐localized immune responses and among others regulates antigen presentation to and by immune cells. Autophagy also directly regulates T and natural killer cell activity and is required for mounting T‐cell memory responses. Thus, within the tumor microenvironment autophagy has a multifaceted role that, depending on the context, may help drive tumorigenesis or may help to support anticancer immune responses. This multifaceted role should be taken into account when designing autophagy‐based cancer therapeutics. In this review, we provide an overview of the diverse facets of autophagy in cancer cells and nonmalignant cells in the cancer microenvironment. Second, we will attempt to integrate and provide a unified view of how these various aspects can be therapeutically exploited for cancer therapy.

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“…In the current investigations we have used endotoxin-free/ultra-pure OVA. Much literature of in vitro experiments shows MDP requires another MAMP to produce measurable outputs like cytokine 7, 41–43 , although in few cases MDP was shown to elicit cellular responses by itself 41, 42 . Responses measured from MDP alone may be unrepresentative of a cell’s maximum capacity.…”

Section: Discussionmentioning

confidence: 99%

Synthetic mycobacterial molecular patterns partially complete Freund’s adjuvant

Dubé

McIntosh

Zarruk

et al. 2019

Preprint

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AbstractComplete Freund’s adjuvant (CFA) has historically been one of the most useful tools of immunologists. Essentially comprised of dead mycobacteria and mineral oil, we asked ourselves what is special about the mycobacterial part of this adjuvant, and could it be recapitulated synthetically? Here, we demonstrate the essentiality of N-glycolylated peptidoglycan plus trehalose dimycolate (both unique in mycobacteria) for the complete adjuvant effect using knockouts and chemical complementation. A combination of synthetic N-glycolyl muramyl dipeptide and minimal trehalose dimycolate motif GlcC14C18 was able to upregulate dendritic cell effectors, plus induce experimental autoimmunity qualitatively similar but quantitatively milder compared to CFA. This research outlines how to substitute CFA with a consistent, molecularly-defined adjuvant which may inform the design of immunotherapeutic agents and vaccines benefitting from cell-mediated immunity. We also anticipate using synthetic microbe-associated molecular patterns (MAMPs) to study mycobacterial immunity and immunopathogenesis.

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Signaling through NOD-2 and TLR-4 Bolsters the T cell Priming Capability of Dendritic cells by Inducing Autophagy

Cited by 41 publications

References 34 publications

Galectin-8 activates dendritic cells and stimulates antigen-specific immune response elicitation

Galectin-8 activates dendritic cells and stimulates antigen-specific immune response elicitation

The multifaceted role of autophagy in cancer and the microenvironment

Synthetic mycobacterial molecular patterns partially complete Freund’s adjuvant

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