Human IDO-competent, long-lived immunoregulatory dendritic cells induced by intracellular pathogen, and their fate in humanized mice

Rajeev K. Tyagi, Brodie Miles, Rajesh Parmar, Neeraj K. Garg, Sarat K. Dalai, Babak Baban, Christopher W Cutler

Research output: Contribution to journalArticle

2 Citations (Scopus)

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 + T-cell and Th1/Th17 effector-responses while inducing CD25 + Foxp3 + CD127 - 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.

Original languageEnglish (US)
Article number41083
JournalScientific Reports
Volume7
DOIs
StatePublished - Feb 15 2017

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Porphyromonas gingivalis
Dendritic Cells
Monocytes
Indoleamine-Pyrrole 2,3,-Dioxygenase
Myeloid Cells
Apoptosis
T-Lymphocytes
Survival
Infection
pyrenedodecanoylcarnitine
In Vitro Techniques
DC-specific ICAM-3 grabbing nonintegrin
5-chloromethylfluorescein

ASJC Scopus subject areas

  • General

Cite this

Human IDO-competent, long-lived immunoregulatory dendritic cells induced by intracellular pathogen, and their fate in humanized mice. / Tyagi, Rajeev K.; Miles, Brodie; Parmar, Rajesh; Garg, Neeraj K.; Dalai, Sarat K.; Baban, Babak; Cutler, Christopher W.

In: Scientific Reports, Vol. 7, 41083, 15.02.2017.

Research output: Contribution to journalArticle

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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 + T-cell and Th1/Th17 effector-responses while inducing CD25 + Foxp3 + CD127 - 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.",
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AU - Miles, Brodie

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AU - Garg, Neeraj K.

AU - Dalai, Sarat K.

AU - Baban, Babak

AU - Cutler, Christopher W

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