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The Role of T cell-associated Polarizing Transcription Factors in Dendritic cell Priming of T cells towards Immunity or Tolerance; role of T-bet or Foxp3 ectopic expression in Dendritic cells

Lipscomb, Michael Wheeler (2009) The Role of T cell-associated Polarizing Transcription Factors in Dendritic cell Priming of T cells towards Immunity or Tolerance; role of T-bet or Foxp3 ectopic expression in Dendritic cells. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Dendritic cells (DC) are professional antigen presenting cells that can prime naïve T cells to elicit immunity or tolerance. The ability to regulate immunity or tolerance is governed by the "type" of polarization state of these activated T cells. T-bet (T-box expressed in T cells) has been identified as the master regulator of Type 1 polarization in T cells, and its expression in T cells is essential for immunity. Conversely, Foxp3 expression in T cells (T regulatory cells) engenders a tolerogenic phenotype that can suppress immunity in Type-1, as well as the Type-2 and -17 subsets, and DC. Interestingly, T-bet is also expressed in DC and its abolishment resulted in impaired Type-1 T cell responses. Furthermore, Foxp3 expression in non-T cell subsets, such as adenocarinoma, has shown potent immunosuppressive characteristics in the tumor microenvironment and draining lymph nodes. Therefore, we examined the role of adenoviral transduced T-bet and Foxp3 in the myeloid cell lineage, specifically monocyte-derived DC. We evaluated the phenotypic expression of DC and T cell responses upon priming by T-bet expressing DC ( or Foxp3 expressing DC (DC.Fox). potently primed naïve T cells towards Type 1 immunity, inducing 2-3 fold increased levels of T-bet, IFNγ, CXCR3, and Granzyme-B. Interestingly, we found little-to-no changes in costimulatory molecule expression. However, DC were completely impaired in production of Type-1-inducing cytokines. We confirmed cytokine-independent Type 1 polarization by using neutralization antibodies. More surprisingly, we found that Foxp3 in DC induced tolerance. Mechanisms included direct suppression of CD8+ T cell subsets and indirect suppression of Type-1 responses by increased generation of T regulatory cell subsets. These generated DC.Fox induced-Tregs (XiTregs) expressed high levels of CTLA-4, CD25, and GITR and concomitantly suppressed naïve and memory CD8+ T cell proliferation and IFNγ production. Neutralizing agents confirmed that tryptophan catabolizing enzyme-IDO and TGFβ were important in suppressing generation of Tregs and effector functions of T cells. In summation, this work shows that T-bet and Foxp3 expression in DC play similar roles to expression in T cells by governing immunity or tolerance. Furthermore, this provides a basis for the usage of these DC in immunotherapies.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Lipscomb, Michael Wheelermil22@pitt.eduMIL22
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairKalinski, Pawelkalinskip@upmc.eduPAK5
Committee MemberMorelli, Adrianmorelli@pitt.eduMORELLI
Committee MemberPiganelli, Jon Djdp51@pitt.eduJDP51
Committee MemberBasse, Per Hbasse@pitt.eduBASSE
Committee MemberStorkus, Walter Jstorkuswj@upmc.eduSTORKUSW
Date: 10 August 2009
Date Type: Completion
Defense Date: 5 August 2009
Approval Date: 10 August 2009
Submission Date: 8 August 2009
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: dendritic cell; foxp3; IL-12; IL-12 independent; polarization; T cell; t-bet; transcription factors
Other ID:, etd-08082009-182900
Date Deposited: 10 Nov 2011 19:58
Last Modified: 19 Dec 2016 14:37


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