Watchmaker, Payal
(2007)
Feedback Interactions between Dendritic Cells and CD8+ T Cells during the Development of Type-1 Immunity.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
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.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Watchmaker, Payal | paw7@pitt.edu | PAW7 | |
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| ETD Committee: |
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| Date: |
16 November 2007 |
| Date Type: |
Completion |
| Defense Date: |
9 October 2007 |
| Approval Date: |
16 November 2007 |
| Submission Date: |
12 November 2007 |
| 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: |
CCR7; Dendritic cells; TNFalpha; CD8+ T cells; IL-12; PI-9; IFNgamma |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-11122007-204524/, etd-11122007-204524 |
| Date Deposited: |
10 Nov 2011 20:04 |
| Last Modified: |
19 Dec 2016 14:37 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/9643 |
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