Alternative activation of dendritic cells
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Date
29/06/2013Author
Jones, Lucy Helen
Metadata
Abstract
The alternative activation of macrophage populations by Interleukin-4 (IL-4) is well
characterised. Alternatively activated macrophages (AAM) express high levels of the
arginine converting enzyme arginase-1, and express a plethora of IL-4 driven
molecules including the resistin like molecule alpha (RELMα) and the chitinase like
molecule Ym1/2. Dendritic cells (DCs) are the professional antigen presenting cells
(APC) of the immune system, responsible for the detection of invading pathogens,
secretion of cytokines and the subsequent activation of T-cells. This thesis
addresses whether IL-4 is able to ‘alternatively activate’ DCs both in vitro and in
vivo, in a manner similar to that of AAM.
The impact of IL-4 on DC and macrophage activation was compared and
contrasted, and it was confirmed for the first time that IL-4 can alternatively activate
DCs, inducing high level expression of a range of alternative activation associated
markers including RELMα, Ym1/2, CCL24 and dectin-1, with the exception of
arginase. DCs were significantly more capable at the in vivo priming of T-cell
responses in the context of both Th1 and Th2 polarising antigens than similarly
exposed macrophages, confirming their superior capacity as APC.
The requirements for DC IL-4Rα expression were assessed, and IL-4
responsiveness was found to be required for the optimal induction of Th1
responses. Conversely, selective loss of only one facet of the IL-4 response, namely
RELMα expression, limited the ability of IL-4 exposed DCs to induce the regulatory
cytokine IL-10 both in vitro and in vivo. Furthermore, alternatively activated DCs
(AADCs) were found in the spleen following 8 weeks of infection with the parasitic
trematode Schistosoma mansoni, highlighting a role for DC alternative activation in
a disease setting.
IL-4 was shown to induce expression of the vitamin A converting enzyme aldehyde
dehydrogenase, and the product of such activity, retinoic acid (RA), was found to
promote the expression of RELMα in IL-4 exposed DCs. Aldehyde dehydrogenase
activity was found to inversely correlate with DC expression of Ym1/2 and inhibition
of RA signalling limited IL-4 driven RELMα and promoted Ym1/2.