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Berk, Erik (2012) DENDRITIC CELLS REGULATE THE INDUCTION OF EFFECTOR AND MEMORY CD8+ T CELLS. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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
CreatorsEmailPitt UsernameORCID
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorKalinski, Pawelkalinskip@upmc.eduPAK5
Committee MemberHendricks, Robert L.hendricksrr@upmc.eduRLH13
Committee MemberStorkus, Walter J.storkuswj@upmc.eduSTORKUSW
Committee MemberWatkins, Simon C.swatkins@pitt.eduSWATKINS
Committee MemberSobol, Robert Wrws9@pitt.eduRWS9
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


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