CD8+ T cell responses are crucial for immunity against intracellular infections and can mediate tumor regression. While CD8+ T cells are widely recognized as cytolytic effector cells (cytolytic T cells; CTLs), little is known about their immunoregulatory functions and their impact on dendritic cells (DCs). A similar area of controversy is the role of DC in regulating the induction of CD8+ T cell effector functions and CD8+ T cell memory. This dissertation addresses the impact of bidirectional communication between DCs and CD8+ T cells, during different phases of the immune response, upon the functions of both these cell types.
In order to reconcile the apparently contrasting notions that CD8+ T cells perform both suppressor and helper functions, I compared the DC-modulating activity of CD8+ T cells at different stages of activation. I observed that DC-killing and DC-activating (and protective) functions are exerted sequentially by activated CD8+ T cells. In contrast to the effector cells that kill DCs in a granzyme B/perforin-dependent manner, memory CD8+ T cells promote IL-12 production in DCs and support CD4+ and CD8+ T cell responses. Moreover, memory CD8+ T cells instruct DC to over-express granzyme B inhibitor PI-9, protecting them from elimination by CTLs. I observed that the inclusion of heterologous CD8+ T cell epitopes in cancer vaccines, promoting the interaction of vaccine-bearing DCs with large numbers of tumor-unrelated CD8+ T cells, strongly enhances the immunologic and therapeutic activity of vaccination against established tumors that are resistant to standard vaccines.
Since the character of the vaccination-induced CD8+ T cells is important for the efficacy of cancer immunotherapy, I have analyzed the role of DCs in influencing the cytolytic function and peripheral tissue-homing ability of CD8+ T cells. I observed that short-term-activated inflammatory-type DCs, capable of producing high levels of IL-12 and other pro-inflammatory cytokines, support induction of cytotoxic function and a switch from lymphoid to peripheral chemokine receptors in CD8+ T cells. In contrast, exhausted DCs matured for extended periods of time or matured under the influence of the mediators of chronic inflammation, favor CD8+ T cell expansion alone without acquisition of effector functions.
Collectively, the findings presented in this dissertation broaden our understanding of the feedback circuitry between CD8+ T cells and DCs and will help us to design improved vaccines against cancer and chronic infections.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-11122007-204524 |
| Date | 16 November 2007 |
| Creators | Watchmaker, Payal |
| Contributors | Lisa H. Butterfield, Albert D. Donnenberg, Todd Reinhart, Charles R. Rinaldo, Walter J. Storkus, Pawel Kalinski |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-11122007-204524/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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