Janelsins, Brian Mark
(2010)
Role of Neurokinin 1 Receptor in Modulating the Immune-Stimulatory Function of Dendritic Cells.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
There is a growing body of evidence indicating that the nervous and immune systems cross-talk during inflammatory and immune responses. Secretion of pro-inflammatory neuropeptides from the tachykinin family, including substance P (SP) and hemokinin-1 (HK-1), favors cellular immunity by binding the neurokinin 1 receptor (NK1R) to promote immune cell survival and activation. Dendritic cells (DCs) are essential for the stimulation of cellular immunity; however, the ability of pro-inflammatory tachykinins to affect the immune-stimulatory function of DCs remains elusive. Since DCs home strategically to peripheral and lymphoid tissues where tachykinins are secreted, we hypothesized that signaling via the NK1R enhances DC longevity and their T cell-stimulatory function, including the induction of type-1 CD4+ T cell helper (Th1) and CD8+ cytotoxic T cell (CTL/Tc1) responses. Using DCs generated from murine bone marrow precursors (BMDCs), I describe that BMDCs express functional NK1R, and agonistic signaling via the receptor rescues BMDCs from apoptosis. The immunological relevance of these findings were validated in vivo, as I demonstrate that adoptive transfer of NK1R-signaled BMDCs loaded with antigen (Ag) migrate efficiently to tissue-draining lymph nodes (DLNs) where they survive longer and induce superior type-1 DTH responses compared to adoptive transfer of control Ag-loaded BMDCs. Secondly, I investigated the mechanisms by which NK1R-signaled BMDCs favor cellular immunity, including their ability to generate Th1 and CTL/Tc1 responses. I show that agonistic signaling via the NK1R promotes the maturation of BMDCs and inhibits their secretion of IL-10, and adoptive transfer of NK1R-signaled BMDCs elicits enhanced Ag-specific Th1 and CTL/Tc1 responses. The individual roles of adoptively transferred NK1R-signaled BMDCs and endogenous DCs were further addressed by comparing the development of type-1 immunity in wild-type, IL-12 knockout (IL-12p35-/-) and Diphtheria Toxin Recetor (DTR) transgenic (inducible depletion of CD11c+ DCs) mice. With these models, I demonstrate that generation of robust Ag-specific Th1 and CTL/Tc1 responses requires secretion of IL-12p70 by endogenous DCs and inhibition of IL-10 production by transferred BMDCs. Collectively, our data strongly suggest that adoptive transfer of NK1R-signaled BMDCs promotes enhanced type-1 immunity by mechanisms involving both exogenous and endogenous DC populations.
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Details
Item Type: |
University of Pittsburgh ETD
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Status: |
Unpublished |
Creators/Authors: |
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ETD Committee: |
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Date: |
4 March 2010 |
Date Type: |
Completion |
Defense Date: |
15 January 2009 |
Approval Date: |
4 March 2010 |
Submission Date: |
10 February 2010 |
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: |
Adoptive transfer; Dendritic cells; Neuropeptides; Type-1 T cell responses; Cellular immunity; Tachykinins; Cell survival |
Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-02102010-114923/, etd-02102010-114923 |
Date Deposited: |
10 Nov 2011 19:31 |
Last Modified: |
19 Dec 2016 14:34 |
URI: |
http://d-scholarship.pitt.edu/id/eprint/6344 |
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