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

5 Scopus citations

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

    Fingerprint

ASJC Scopus subject areas

  • General

Cite this