Berk, Erik
(2012)
DENDRITIC CELLS REGULATE THE INDUCTION OF EFFECTOR AND MEMORY CD8+ T CELLS.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Dendritic cells (DCs) are key antigen-presenting cells in the immune system that can induce pathogen-specific T cell responses by presenting antigen (signal 1) to antigen-specific T cells in combination with co-stimulatory/inhibitory molecules (signal 2) and secretion of cytokines (signal 3). The ability of DCs to orchestrate CD8+ T cell responses, combined with the ability to generate high numbers of DCs in vitro allows for their use in DC-based vaccination protocols. The success of DC-based vaccination protocols and other forms of immunotherapy of cancer is believed to depend on the successful induction of both effector CD8+ T cell (CTLs), able to migrate into and kill tumors, and long-lived memory cells, able to generate a secondary response upon tumor recurrence. However, the signals that drive the differentiation of CD8+ T cells into each of these T cell subsets and the role of DCs in this respect remain unclear. Studies have suggested that the same DC can induce effector cells early after maturation while inducing memory cells after prolonged maturation when the DCs have become exhausted.
Here, I analyzed the role of DCs matured under conditions mimicking acute/early inflammation (“inflammatory-DCs”) or mimicking chronic/late inflammation (“non-inflammatory-DCs”) on the differentiation of CD8+ T cells. I observed that “inflammatory-DCs” produce high levels of IL-12p70 and induce the differentiation of naïve CD8+ T cell into cytolytic effector cells with peripheral homing ability. Furthermore, I demonstrate the role of IL-12p70 in this process. In contrast, “non-inflammatory-DCs” (exhausted DCs) do not produce IL-12p70 and induce the direct differentiation of naïve CD8+ T cells into central-memory cells. The superior ability of “inflammatory-DCs” to induce anti-tumor responses guided me to develop an alternative, low-cost method of generating “inflammatory-DCs” with strong CTL inducing ability. Lastly, I show that modulation of the tumor-chemokine environment by IFN, poly-I:C and indomethacin enhanced the attraction of tumor-specific CTLs while reducing regulatory T cell attraction.
Together, the presented data broadens our understanding of the mechanisms of DC-induced effector and memory cell differentiation and might lead to the improved DC-based cancer vaccines.
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| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
16 August 2012 |
| Date Type: |
Publication |
| Defense Date: |
2 August 2012 |
| Approval Date: |
16 August 2012 |
| Submission Date: |
16 August 2012 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Number of Pages: |
179 |
| 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 cells, IL-12, CD8+ T cells, central-memory |
| Date Deposited: |
16 Aug 2012 19:02 |
| Last Modified: |
16 Aug 2017 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/13615 |
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