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Novel Mechanisms In Dendritic Cells That Promote Th2 and Th17 But Not Th1 Responses In The Lung

Krishnamoorthy, Nandini (2008) Novel Mechanisms In Dendritic Cells That Promote Th2 and Th17 But Not Th1 Responses In The Lung. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Dendritic cells (DCs) are integral to differentiation of T helper cells into Th1, Th2 and Th17 subsets. We have dissected two novel pathways in DCs that specifically regulate CD4 T cell responses. The first is the role of the c-Kit-Phosphatidyl inositol 3 kinase (PI3 kinase)-interleukin-6 (IL-6) axis and the second that of vascular endothelial growth factor (VEGF). IL-6 plays a central role in regulating CD4 T cell immune responses by limiting a Th1 response and promoting Th2 and Th17 responses. We investigate pathways in DCs that promote IL-6 production and show that the allergen house dust mite or the mucosal adjuvant cholera toxin but not Th1-inducing adjuvant, CpG oligodeoxynucleotide (ODN) promote cell surface expression of c-kit and its ligand, stem cell factor (SCF), in DCs. This dual upregulation of c-kit and SCF results in sustained PI3-kinase signaling promoting IL-6 secretion. Intranasal administration of antigen into c-kit mutant mice or neutralization of IL-6 blunted Th2 and Th17 but promoted Th1 responses in lung-draining lymph nodes. DCs lacking functional c-kit elicit diminished allergic airway inflammation when adoptively transferred into mice. Expression of the Notch ligand, Jagged-2, which has been associated with Th2 differentiation, was reduced in DCs from c-kit mutant mice. DCs generated from mice expressing a catalytically inactive form of the p110ƒÔ (p110D910A) subunit of PI3-kinase secrete lower levels of IL-6 upon stimulation with CT. These results collectively highlight the importance of the c-kit-PI3-kinase-IL-6 signaling axis in DCs in regulating T cell responses.We also investigated mechanisms underlying the production of VEGF, which has been recently shown to be a Th2-skewing cytokine and to promote allergic asthma. We found that CT-stimulated DCs secrete high levels of VEGF while LPS induces minimal VEGF production. Activation of iNOS, NF-ƒÛB and PI3 kinase enhanced production of VEGF in DCs whereas IL-12, a Th1-skewing cytokine, inhibited VEGF production. This mechanism highlights a critical but previously unknown role for DC-derived VEGF. Taken together, these findings broaden our understanding of diverse mechanisms in DCs that enable T cell polarization and offer novel targets for therapeutic interventions.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Krishnamoorthy, Nandininkm6@pitt.eduNKM6
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairRay, Prabirrayp@pitt.eduRAYP
Committee MemberRay, Anuradharaya@pitt.eduRAYA
Committee MemberLu, Binfengbinfeng@pitt.eduBINFENG
Committee MemberKolls, JayJay.Kolls@chp.eduJKK23
Committee MemberSalter, Russellrds@pitt.eduRDS
Date: 15 May 2008
Date Type: Completion
Defense Date: 21 April 2008
Approval Date: 15 May 2008
Submission Date: 5 May 2008
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: c-kit; IL-6; notch ligand; stem cell factor; VEGF
Other ID:, etd-05052008-123146
Date Deposited: 10 Nov 2011 19:43
Last Modified: 19 Dec 2016 14:35


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