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Human IDO-competent, long-lived immunoregulatory dendritic cells induced by intracellular pathogen, and their fate in humanized mice.
- Source :
-
Scientific reports [Sci Rep] 2017 Feb 15; Vol. 7, pp. 41083. Date of Electronic Publication: 2017 Feb 15. - Publication Year :
- 2017
-
Abstract
- Targeting of myeloid-dendritic cell receptor DC-SIGN by numerous chronic infectious agents, including Porphyromonas gingivalis, is shown to drive-differentiation of monocytes into dysfunctional mDCs. These mDCs exhibit alterations of their fine-tuned homeostatic function and contribute to dysregulated immune-responses. Here, we utilize P. gingivalis mutant strains to show that pathogen-differentiated mDCs from primary human-monocytes display anti-apoptotic profile, exhibited by elevated phosphorylated-Foxo1, phosphorylated-Akt1, and decreased Bim-expression. This results in an overall inhibition of DC-apoptosis. Direct stimulation of complex component CD40 on DCs leads to activation of Akt1, suggesting CD40 involvement in anti-apoptotic effects observed. Further, these DCs drove dampened CD8 <superscript>+</superscript> T-cell and Th1/Th17 effector-responses while inducing CD25 <superscript>+</superscript> Foxp3 <superscript>+</superscript> CD127 <superscript>-</superscript> Tregs. In vitro Treg induction was mediated by DC expression of indoleamine 2,3-dioxygenase, and was confirmed in IDO-KO mouse model. Pathogen-infected &CMFDA-labeled MoDCs long-lasting survival was confirmed in a huMoDC reconstituted humanized mice. In conclusion, our data implicate PDDCs as an important target for resolution of chronic infection.
- Subjects :
- Animals
Apoptosis
Bcl-2-Like Protein 11 metabolism
CD40 Antigens metabolism
CD8-Positive T-Lymphocytes cytology
CD8-Positive T-Lymphocytes immunology
CD8-Positive T-Lymphocytes metabolism
Cell Differentiation
Cytokines metabolism
Dendritic Cells metabolism
Dendritic Cells microbiology
Forkhead Box Protein O1 metabolism
Humans
Indoleamine-Pyrrole 2,3,-Dioxygenase deficiency
Indoleamine-Pyrrole 2,3,-Dioxygenase genetics
Indoleamine-Pyrrole 2,3,-Dioxygenase metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Monocytes cytology
Monocytes metabolism
Porphyromonas gingivalis genetics
Proto-Oncogene Proteins c-akt metabolism
T-Lymphocytes, Regulatory cytology
T-Lymphocytes, Regulatory immunology
T-Lymphocytes, Regulatory metabolism
Th1 Cells immunology
Th1 Cells metabolism
Th17 Cells cytology
Th17 Cells immunology
Th17 Cells metabolism
Dendritic Cells immunology
Porphyromonas gingivalis pathogenicity
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 7
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 28198424
- Full Text :
- https://doi.org/10.1038/srep41083