PE_PGRS Antigens of<i>Mycobacterium tuberculosis</i>Induce Maturation and Activation of Human Dendritic Cells

Bansal, Kushagra; Elluru, Sri Ramulu; Narayana, Y.; Chaturvedi, Rashmi; Patil, Shripad A.; Kaveri, Srini V.; Bayry, Jagadeesh; Balaji, Kithiganahalli Narayanaswamy

doi:10.4049/jimmunol.0903299

Cited by 105 publications

(105 citation statements)

References 68 publications

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“…Accordingly, we could not detect endotoxins in agonist preparations as analyzed by E-Toxate kit (Sigma). Furthermore, as demonstrated previously, unrelated mycobacterial lipase protein produced and processed by the same procedure did not demonstrate the ability to induce expression of maturation markers on DCs (15). Significantly, treatment of Rv0754 with proteinase K abolished the ability of Rv0754 to trigger maturation of DCs suggesting the requirement of intact protein in its native form for inducing the maturation of DCs (15).…”

Section: Tlr2 and Nod Receptors Cooperativelymentioning

confidence: 75%

“…We have previously demonstrated that Rv0754, a prototype member of the PE_PGRS family of M. tuberculosis recognizes TLR2 and induces maturation and activation of human DCs (15). Furthermore, NOD1 and NOD2 agonists in concert with TLRs have been shown to direct Th1 lineage commitment of ensuing immune responses (6).…”

Section: Tlr2 and Nod Receptors Cooperativelymentioning

confidence: 99%

“…ϩ monocytederived human DCs were obtained from healthy donors as described previously (15). Briefly, human peripheral blood mononuclear cells were isolated from buffy coats of healthy donors obtained from Hôpital Hôtel Dieu, Etablissement Français du Sang, Paris, France, upon ethical approval for the use of such materials.…”

Section: Generation and Culture Of Human Dcs-cd14mentioning

confidence: 99%

“…TLR2 receptors, while acting as sensors for extracellular cues or the endocytic network, drive signaling events in response to recognition of pathogen-associated molecular patterns, including mycobacterial antigens like ESAT-6, PE_PGRS antigens; NOD1 and NOD2 operate as cytosolic sensors initiating signaling pathways upon recognition of diaminopimelic acid and muramyl dipeptide (MDP), components of bacterial peptidoglycan (15)(16)(17)(18)(19)(20). Although TLR2 or NOD receptor-induced signaling events culminate in activation and nuclear translocation of NF-B, transcriptome profiles in response to TLR2 or NOD receptors could markedly diverge.…”

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confidence: 99%

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Cooperative Regulation of NOTCH1 Protein-Phosphatidylinositol 3-Kinase (PI3K) Signaling by NOD1, NOD2, and TLR2 Receptors Renders Enhanced Refractoriness to Transforming Growth Factor-β (TGF-β)- or Cytotoxic T-lymphocyte Antigen 4 (CTLA-4)-mediated Impairment of Human Dendritic Cell Maturation

Ghorpade

Kaveri

Bayry

et al. 2011

Journal of Biological Chemistry

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Dendritic cells (DCs) as sentinels of the immune system are important for eliciting both primary and secondary immune responses to a plethora of microbial pathogens. Cooperative stimulation of a complex set of pattern-recognition receptors, including TLR2 and nucleotide-binding oligomerization domain (NOD)-like receptors on DCs, acts as a rate-limiting factor in determining the initiation and mounting of the robust immune response. It underscores the need for "decoding" these multiple receptor interactions. In this study, we demonstrate that TLR2 and NOD receptors cooperatively regulate functional maturation of human DCs. Intriguingly, synergistic stimulation of TLR2 and NOD receptors renders enhanced refractoriness to TGF-␤-or CTLA-4-mediated impairment of human DC maturation. Signaling perturbation data suggest that NOTCH1-PI3K signaling dynamics assume critical importance in TLR2-and NOD receptor-mediated surmounting of CTLA-4-and TGF-␤-suppressed maturation of human DCs. Interestingly, the NOTCH1-PI3K signaling axis holds the capacity to regulate DC functions by virtue of PKC␦-MAPK-dependent activation of NF-B. This study provides mechanistic and functional insights into TLR2-and NOD receptor-mediated regulation of DC functions and unravels NOTCH1-PI3K as a signaling cohort for TLR2 and NOD receptors. These findings serve in building a conceptual foundation for the design of improved strategies for adjuvants and immunotherapies against infectious diseases.

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Section: Tlr2 and Nod Receptors Cooperativelymentioning

confidence: 75%

Section: Tlr2 and Nod Receptors Cooperativelymentioning

confidence: 99%

Section: Generation and Culture Of Human Dcs-cd14mentioning

confidence: 99%

mentioning

confidence: 99%

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Cooperative Regulation of NOTCH1 Protein-Phosphatidylinositol 3-Kinase (PI3K) Signaling by NOD1, NOD2, and TLR2 Receptors Renders Enhanced Refractoriness to Transforming Growth Factor-β (TGF-β)- or Cytotoxic T-lymphocyte Antigen 4 (CTLA-4)-mediated Impairment of Human Dendritic Cell Maturation

Ghorpade

Kaveri

Bayry

et al. 2011

Journal of Biological Chemistry

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“…In addition, DCs are the APCs in immunotherapy that can effectively present the Ag of a vaccine. Recently, it has been reported that certain Ags of the BCG vaccine can activate DCs through the TLR4 and TLR2 pathways and increase the differentiation and activity of CTLs (3)(4)(5)(6)(7). Previously, we reported an increase in the survival rate in an E.G7 thymoma model in which mice were vaccinated with DCs, and heparinbinding hemagglutinin protein extracted from Mycobacterium tuberculosis was used to stimulate the TLR4 levels (6).…”

mentioning

confidence: 99%

Enhancement of Tumor-Specific T Cell–Mediated Immunity in Dendritic Cell–Based Vaccines by Mycobacterium tuberculosis Heat Shock Protein X

Jung

Shin

Lee

et al. 2014

The Journal of Immunology

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Despite the potential for stimulation of robust antitumor immunity by dendritic cells (DCs), clinical applications of DC-based immunotherapy are limited by the low potency in generating tumor Ag-specific T cell responses. Therefore, optimal conditions for generating potent immunostimulatory DCs that overcome tolerance and suppression are key factors in DC-based tumor immunotherapy. In this study, we demonstrate that use of the Mycobacterium tuberculosis heat shock protein X (HspX) as an immunoadjuvant in DC-based tumor immunotherapy has significant potential in therapeutics. In particular, the treatment aids the induction of tumor-reactive T cell responses, especially tumor-specific CTLs. The HspX protein induces DC maturation and proinflammatory cytokine production (TNF-α, IL-1β, IL-6, and IFN-β) through TLR4 binding partially mediated by both the MyD88 and the TRIF signaling pathways. We employed two models of tumor progression and metastasis to evaluate HspX-stimulated DCs in vivo. The administration of HspX-stimulated DCs increased the activation of naive T cells, effectively polarizing the CD4+ and CD8+ T cells to secrete IFN-γ, as well as enhanced the cytotoxicity of splenocytes against HPV-16 E7 (E7)–expressing TC-1 murine tumor cells in therapeutic experimental animals. Moreover, the metastatic capacity of B16-BL6 melanoma cancer cells toward the lungs was remarkably attenuated in mice that received HspX-stimulated DCs. In conclusion, the high therapeutic response rates with tumor-targeted Th1-type T cell immunity as a result of HspX-stimulated DCs in two models suggest that HspX harnesses the exquisite immunological power and specificity of DCs for the treatment of tumors.

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An overview to understand the role of PE_PGRS family proteins in Mycobacterium tuberculosisH₃₇Rv and their potential as new drug targets

Meena

2014

Biotech and App Biochem

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Tuberculosis has long been the scourge of humanity, claiming millions of lives. The family of PE_PGRS gene has been attributed to the Mycobacterium tuberculosis pathogenesis over the past few decades. The gene of PE_PGRS family proteins are most often clustered in a region of the genome often as overlapping genes and role in cell surface markers, adhesion and invasion of defense cells of the host (macrophage and dendritic cells). The proline-glutamic acid (PE) domain is responsible for the cellular localization of these proteins on bacterial cells. This gene family shows immense genetic variability in terms of multiple insertion-deletions and single-nucleotide polymorphisms as seen in PE_PGRS9, PE_PGRS17, PE_PGRS18, and PE_PGRS33. In spite of variability, there are indications of shared epitopes in these proteins. Few of these gene sequences that have been studied from evolutionary perspective show indication of positive selection and also landmarks of recent evolutionary events. Many of these proteins show calcium-binding motifs and consequently seen to be responsible in inhibition of phagolysosome formation via a calmodulin-kinase-dependent pathway. A number of PE_PGRS genes were tested for its expression with different growth conditions in vitro and in vivo, among which the contrast in expressivity was seen vividly in PE_PGRS16 (upregulated) and PE_PGRS26 (downregulated) in bacteria persisting in macrophages. Similarly, PE_PGRS33 has been indicated in macrophagial necrosis by a tumor necrosis factor-α-induced pathway. These PE_PGRS family genes may be an interesting subject for research and development. Their fibronectin-binding and calcium-binding property may be strongly implicated in immunopathogenesis of virulent M. tuberculosis strain. In this review, an attempt has been made to evaluate and present data for better understanding of in vivo pathogen functions, for understanding the physiological significance of PE_PGRS gene family, and their potential as new drug targets.

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PE_PGRS Antigens ofMycobacterium tuberculosisInduce Maturation and Activation of Human Dendritic Cells

Abstract: Material

Cited by 105 publications

References 68 publications

Cooperative Regulation of NOTCH1 Protein-Phosphatidylinositol 3-Kinase (PI3K) Signaling by NOD1, NOD2, and TLR2 Receptors Renders Enhanced Refractoriness to Transforming Growth Factor-β (TGF-β)- or Cytotoxic T-lymphocyte Antigen 4 (CTLA-4)-mediated Impairment of Human Dendritic Cell Maturation

Cooperative Regulation of NOTCH1 Protein-Phosphatidylinositol 3-Kinase (PI3K) Signaling by NOD1, NOD2, and TLR2 Receptors Renders Enhanced Refractoriness to Transforming Growth Factor-β (TGF-β)- or Cytotoxic T-lymphocyte Antigen 4 (CTLA-4)-mediated Impairment of Human Dendritic Cell Maturation

Enhancement of Tumor-Specific T Cell–Mediated Immunity in Dendritic Cell–Based Vaccines by Mycobacterium tuberculosis Heat Shock Protein X

An overview to understand the role of PE_PGRS family proteins in Mycobacterium tuberculosisH₃₇Rv and their potential as new drug targets

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PE_PGRS Antigens ofMycobacterium tuberculosisInduce Maturation and Activation of Human Dendritic Cells

Abstract: Material

Cited by 105 publications

References 68 publications

Cooperative Regulation of NOTCH1 Protein-Phosphatidylinositol 3-Kinase (PI3K) Signaling by NOD1, NOD2, and TLR2 Receptors Renders Enhanced Refractoriness to Transforming Growth Factor-β (TGF-β)- or Cytotoxic T-lymphocyte Antigen 4 (CTLA-4)-mediated Impairment of Human Dendritic Cell Maturation

Cooperative Regulation of NOTCH1 Protein-Phosphatidylinositol 3-Kinase (PI3K) Signaling by NOD1, NOD2, and TLR2 Receptors Renders Enhanced Refractoriness to Transforming Growth Factor-β (TGF-β)- or Cytotoxic T-lymphocyte Antigen 4 (CTLA-4)-mediated Impairment of Human Dendritic Cell Maturation

Enhancement of Tumor-Specific T Cell–Mediated Immunity in Dendritic Cell–Based Vaccines by Mycobacterium tuberculosis Heat Shock Protein X

An overview to understand the role of PE_PGRS family proteins in Mycobacterium tuberculosisH37Rv and their potential as new drug targets

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An overview to understand the role of PE_PGRS family proteins in Mycobacterium tuberculosisH₃₇Rv and their potential as new drug targets