Activation of Lysosomal Function During Dendritic Cell Maturation

Trombetta, E. Sergio; Ebersold, Melanie; Garrett, Wendy S.; Pypaert, Marc; Mellman, Ira

doi:10.1126/science.1080106

Cited by 646 publications

(575 citation statements)

References 39 publications

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“…29,30 In conclusion, the above arguments collectively convince about the strength of data. However, as in the case of an association being (7) 13/23 (10) 1234 Â 1234 a (9) 13/24 (11) a…”

Section: Discussionmentioning

confidence: 99%

“…[8][9][10][11][12][13][14][15] The study was extended to six SNPs (rs36027301, rs4147779, rs2471829, rs4147778, rs4147780 and rs2075609), which are not found in patients affected with osteopetrosis. 4 The corresponding alleles were therefore expected to be present in the population at a reasonable frequency.…”

Section: Methodsmentioning

confidence: 99%

“…8 Exclusion of V-ATPase from phagosomes also blocks the processing of Mycobacterium antigens by the macrophages. [7][8][9] Thus, M. tuberculosis curbs both the functions of macrophages, as phagocytic cells and as antigenpresenting cells. In addition, V-ATPase suppresses the expression of macrophage-derived pro-inflammatory cytokines, in particular of TNF-a, 10 which is essential for the control of M. tuberculosis infection: too little as well as too much production of this cytokine predisposes to pulmonary tuberculosis.…”

Section: Introductionmentioning

confidence: 99%

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Human V-ATPase gene can protect or predispose the host to pulmonary tuberculosis

et al. 2009

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Patients (305 patients with pulmonary tuberculosis) and controls (290 household genetically unrelated contacts) were tested by polymerase chain reaction (PCR) for polymorphisms in the intron 15 and the 5 0 untranslated region of the gene coding for the a3 isoform of the human ATPase gene. Diagnosis of pulmonary tuberculosis was based on chest radiography and sputum smear examination and confirmed by PCR and bacteriological tests. Alleles (two at each site) segregated in the form of four haplotype pairs: 13, 14 (very rare), 23, and 24. The 13/24 (double heterozygous) patients were protected against tuberculosis (OR: 0.15; P: 10 À8 ; CI: 0.08-0.3). The 13/13 vs 13/24 and 23/23 vs 23/24 (double homozygous) patients were susceptible to the disease (OR. 5.8; P: 6 Â 10 À7 ; CI: 2.8-11.9; OR: 4.5; P: 5 Â 10 À7 ; CI: 2.5-8.4, respectively).

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“…29,30 In conclusion, the above arguments collectively convince about the strength of data. However, as in the case of an association being (7) 13/23 (10) 1234 Â 1234 a (9) 13/24 (11) a…”

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Human V-ATPase gene can protect or predispose the host to pulmonary tuberculosis

et al. 2009

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“…To elucidate the mechanism of Ag presentation in mDCs delivered by R8-Lip, the mature cells were incubated with lactacystin (a specific proteasome inhibitor) or leupeptin (an endosomal proteases inhibitor). Only lactacystin showed the markedly inhibition of pMHC presentation ( reported that the induction of maturation lowers endosomal/ lysosomal pH by ~1 pH unit, from pH 5.5 to pH 4.5 [34,35]. The acidified endosomes of mDCs may be preferable for R8-Lip-OVA escape from endosomal compartments.…”

Section: Discussionmentioning

confidence: 99%

Enhanced antigen presentation and CTL activity by transduction of mature rather than immature dendritic cells with octaarginine-modified liposomes

Homhuan

Kogure

Nakamura

et al. 2009

Journal of Controlled Release

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To improve uptake and cross-presentation of exogenous antigens (Ag) by dendritic cells (DCs), octaarginine-modified liposomes (R8-Lip) were used as a novel strategy for protein-Ag transduction. Immature DCs endocytose macromolecules efficiently. While mature DCs lose their ability to capture Ag, but have an increased capacity for T-cell activation. Thus Ag-transduction has been performed mostly in immature DCs. In the present study, R8-Lip were efficiently taken up by both immature and mature DCs.DCs transduced after maturation were highly efficient at cross-presentation of Ag and induced higher cytotoxic T-lymphocytes (CTL) activity than were DCs transduced before maturation. The mechanism of Ag presentation involved the escape of R8-Lip from endosomes to cytosol, which require the acidic environment. The Ag released was then processed by a proteasome-dependent pathway. This novel transduction approach is clinically applicable, easy to perform, and has more practical advantages than current protein transduction methods.

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“…The maturation of dendritic cells is associated with a substantial increase in V-ATPase activity, regulated mainly by recruitment of inactive subunits. 26 Interestingly, a recent study has demonstrated that expression of the d2-subunit of V-ATPase is restricted to subsets of dendritic cells, suggesting that alterations in subunit expression may not only regulate enzyme activity but also influence immune cell differentiation and function. 27 The G2 isoform mRNA has been detected in a number of tissues with the highest expression seen in the nervous system.…”

Section: Discussionmentioning

confidence: 99%

Haplotype-specific gene expression profiles in a telomeric major histocompatibility complex gene cluster and susceptibility to autoimmune diseases

et al. 2006

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The telomeric class III region of the major histocompatibility complex is gene dense, but apart from the three tumour necrosis factor (TNF) superfamily members (TNF, lymphotoxin alpha and lymphotoxin beta) little is known of the expression and function of the majority of the genes. Recent genetic studies in autoimmune diseases, particularly rheumatoid arthritis (RA), have suggested a human leukocyte antigen (HLA)-DR-independent disease effect in this region. To gain further insights into these associations, we used lipopolysaccharide-stimulated human macrophages to examine inducible mRNA expression and genotype-phenotype relationships for genes in this region. Following stimulation in addition to the expected induction of TNF mRNA, a 14-fold increase of ATP6V1G2 at 18 h (Po0.001) was seen, whereas B-associated transcript (BAT)2 (Po0.001) and leucocyte-specific transcript (LST)1 (Po0.001) were both downregulated. By genotyping single-nucleotide polymorphisms spanning a 70 kb interval centred on the TNF locus, we constructed haplotypes and determined associated expression profiles for 10 genes in the cluster using quantitative real-time polymerase chain reaction. Overexpression of BAT1 mRNA was associated with carriers of a haplotype containing the LST1 marker transmitted to RA cases in a family study and also DRB1*15 associated with susceptibility to nephritis in systemic lupus erythematosus. The implications of our findings for the understanding of genetic associations with disease susceptibility in this region are discussed.

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Activation of Lysosomal Function During Dendritic Cell Maturation

Cited by 646 publications

References 39 publications

Human V-ATPase gene can protect or predispose the host to pulmonary tuberculosis

Human V-ATPase gene can protect or predispose the host to pulmonary tuberculosis

Enhanced antigen presentation and CTL activity by transduction of mature rather than immature dendritic cells with octaarginine-modified liposomes

Haplotype-specific gene expression profiles in a telomeric major histocompatibility complex gene cluster and susceptibility to autoimmune diseases

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