Objective
The vertebrate immune system has long been considered as a bipartite entity encompassing two independent and isolated arms: innate immunity, providing the first line of defense, and adaptive immunity, responsible for memory. Recent evidence suggests that, in addition to their undisputed role in innate immunity, natural killer (NK) cells and plasmacytoid dendritic cells (pDCs) are important contributors to adaptive immune responses. Yet the mechanisms underlying these cellular interactions are still obscure.
Lately, we could demonstrate a key role for NK cells in the initiation of adaptive immunity by describing a novel pathway harnessing NK cell cytotoxicity for robust T and B cell priming. Interestingly, this sterile inflammatory response was found to be entirely abrogated in mice lacking Toll like receptor (TLR) signaling. As TLRs also sense commensal bacteria, we propose to use germ-free mice to address the role of the normal flora in this sterile pathway induced by NK cells (Aim 1).
Using a new mouse model allowing unbiased assessment of plasmacytoid dendritic cell (pDC) function, we have preliminary data suggesting that in sterile conditions pDCs negatively modulate NK cells and the subsequent priming of adaptive immune effectors. In apparent conflict with these findings, we observed that pDC deficiency in a model of chronic virus infection leads to defective priming of T cells. Such reduced T cell response was preceded by a substantial decrease in cytokine production, most likely as a consequence of diminished NK cell activity. We want to mechanistically address these unexpected and opposite outcomes that are possibly contingent on the nature of the inflammatory environment (Aim 2).
Therefore, by providing a deeper insight into the routes of communication used by effectors of the innate and adaptive immunity, our investigation may reveal novel strategies for the immune–modulation of infections, tumor surveillance or autoimmune diseases.
Fields of science
Call for proposal
FP7-PEOPLE-2012-CIG
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Coordinator
3012 Bern
Switzerland