?url_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Adc&rft.relation=http%3A%2F%2Fd-scholarship-dev.library.pitt.edu%2F31583%2F&rft.title=Programming+Dendritic+cells+for+intercellular+delivery+of+T-bet+to+enhance+function+of+cytotoxic+T-cells&rft.creator=Ravikumar%2C+Pranali&rft.description=Advances+in+antiretroviral+therapy+(ART)+have+proven+successful+for+controlling+HIV-1+in+chronically+infected+individuals.+Despite+these+advancements%2C+curing+HIV-1+infection+poses+a+major+public+health+challenge+due+to+the+establishment+and+maintenance+of+HIV-1+latency+in+long+lasting+memory+CD4%2B+T+cells+during+ART.+Moreover%2C+the+cytotoxic+T+cells+(CTL)+needed+to+effectively+target+and+kill+infected+cells+often+become+exhausted+because+of+chronic+activation.+Interestingly%2C+CTL+from+HIV+elite+controllers+show+less+evidence+exhaustion%2C+which+is+also+associated+with+higher+levels+of+expression+of+the+Th1-associated+transcription+factor+T-bet.+In+this+study%2C+we+hypothesize+that+type-1+polarized+human+dendritic+cells+(DC1)+are+superior+in+their+capacity+to+induce+and+enhance+cellular+immune+responses+against+virally+infected+cells+partially+due+to+their+capacity+to+express+and+transfer+DC-derived+T-bet+to+effector+T+cells.+Moreover%2C+we+propose+that+overexpression+of+T-bet+in+therapeutic+DC%2C+through+genetic+modification%2C+offers+another+approach+to+improve+DC-induced+cellular+immunity.+Here+we+show+that+DC1+indeed+uniquely+express+T+bet+as+a+general+trait+while+conventional+DC+generated+in+the+presence+of+PGE2+(DC2)+are+T-bet+deficient+as+determined+by+western+blot+and+intracellular+flow+cytometry+analysis.+We+also+report+that+overexpression+of+T-bet+in+DC1+(DC1Tbet)+through+use+of+an+adenoviral+vector+delivery+system+enhances+their+CTL+inducing+activity.+However%2C+DC1Tbet+display+a+reduction+in+their+capacity+to+produce+IL-12p70+upon+activation+with+CD40L.+Moreover%2C+using+a+GFP-based+tracking+method%2C+we+demonstrate+that+DC1+have+the+capacity+to+directly+transfer+cytoplasmic+content+to+activated+CD8%2B+T+cells+in+a+CD40L+dependent+manner.+These+data+suggest%2C+both+a+novel+helper+function+of+CD40L+expressing+CD4%2B+Th+cells%2C+and+a+mechanism+for+potential+DC+to+T+cell+transfer+of+T-bet.+We+propose+that+this+immune+mechanism+of+DC1+to+CTL+intercellular+transfer+can+be+exploited+to+enhance+anti-HIV+T+cell+response%2C+or+to+correct+their+dysfunction+of+T+cell+exhaustion+as+supported+by+evidence+in+DC1-based+cancer+immunotherapy+studies+and+help+develop+a+better+understanding+of+intercellular+communication+routes+in+both+health+and+disease+demonstrating+the+significance+of+this+research+in+public+health.&rft.date=2017-06-30&rft.type=University+of+Pittsburgh+ETD&rft.type=PeerReviewed&rft.format=application%2Fpdf&rft.language=en&rft.identifier=http%3A%2F%2Fd-scholarship-dev.library.pitt.edu%2F31583%2F1%2FPRANALI%2520RAVIKUMAR_MSthesis_4_2016.pdf&rft.identifier=++Ravikumar%2C+Pranali++(2017)+Programming+Dendritic+cells+for+intercellular+delivery+of+T-bet+to+enhance+function+of+cytotoxic+T-cells.++Master's+Thesis%2C+University+of+Pittsburgh.++++(Unpublished)++