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.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-02102010-114923 |
| Date | 04 March 2010 |
| Creators | Janelsins, Brian Mark |
| Contributors | Lawrence P. Kane, Russell D. Salter, Paul D. Robbins, Adriana T. Larregina, Walter J. Storkus |
| 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-02102010-114923/ |
| 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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