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(Unpublished)
Abstract
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 (DC.bet) or Foxp3 expressing DC (DC.Fox). DC.bet 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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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Lipscomb, Michael Wheeler | mil22@pitt.edu | MIL22 | |
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| ETD Committee: |
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| 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: |
http://etd.library.pitt.edu/ETD/available/etd-08082009-182900/, etd-08082009-182900 |
| Date Deposited: |
10 Nov 2011 19:58 |
| Last Modified: |
19 Dec 2016 14:37 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/9000 |
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