title: Human IDO-competent, long-lived immunoregulatory dendritic cells induced by intracellular pathogen, and their fate in humanized mice.
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.
authors.affiliation: Department of Periodontics, College of Dental Medicine, Georgia Regents University, Augusta, GA 30912, USA.|Institute of Science, Nirma University, Sarkhej-Gandhinagar Highway, Ahmedabad 382481, Gujarat, India.
authors.forename: Rajeev K
authors.initials: RK
authors.lastname: Tyagi
authors.affiliation: Division of Infectious Diseases, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Brodie
authors.initials: B
authors.lastname: Miles
authors.affiliation: Institute of Science, Nirma University, Sarkhej-Gandhinagar Highway, Ahmedabad 382481, Gujarat, India.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Parmar
authors.affiliation: Drug Delivery Research Group, University Institute of Pharmaceutical Sciences, UGC center of Advanced Studies, Panjab University, Chandigarh, India.
authors.forename: Neeraj K
authors.initials: NK
authors.lastname: Garg
authors.affiliation: Institute of Science, Nirma University, Sarkhej-Gandhinagar Highway, Ahmedabad 382481, Gujarat, India.
authors.forename: Sarat K
authors.initials: SK
authors.lastname: Dalai
authors.affiliation: Department of Oral Biology, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Babak
authors.initials: B
authors.lastname: Baban
authors.affiliation: Department of Periodontics, College of Dental Medicine, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Cutler
mesh_terms: D000818:Animals; D017209:Apoptosis; D000072224:Bcl-2-Like Protein 11 / Q000378:metabolism; D019013:CD40 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D000071161:Forkhead Box Protein O1 / Q000378:metabolism; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D016966:Porphyromonas gingivalis / Q000235:genetics / Q000472:pathogenicity*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: D000072224:Bcl-2-Like Protein 11; D019013:CD40 Antigens; D016207:Cytokines; D000071161:Forkhead Box Protein O1; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D051057:Proto-Oncogene Proteins c-akt