| Summary: | The recent discovery of intracellular complement activation, specifically anaphylatoxin generation and downstream autocrine receptor engagement in conventional α/β CD4+ T cells has provided new insights into mechanisms of T cell activation, polarisation, and homeostatic survival. Anaphylatoxin generation by antigen-presenting cells (APCs) which leads to paracrine signalling via anaphylatoxin receptors on T cells has also been observed but is less extensively described. It is speculated that cell-derived complement may also influence the activity of non-conventional α/β T cells, specifically invariant Natural Killer T (iNKT) cells. The modulation of iNKT cell effector function by cell-derived complement may manifest in two ways, either through autocrine signalling events or via paracrine signalling by neighbouring APCs. Through a combination of molecular biology approaches, a thorough appraisal of iNKT complement expression profiles was performed. Specifically, iNKT cells were shown to up-regulate C3 and the anaphylatoxin receptors C3aR and C5aR1 on their cell surface upon activation with the canonical ligand α-GalCer. Moreover, iNKT cells may ‘recycle’ C3 from the extracellular space, to potentially regulate complement in their local microenvironment. As iNKT cells mature dendritic cells (DC) in a CD40L-dependent manner, subsequent work showed that engagement of the CD40-CD40L axis also influenced DC complement expression profiles. Specifically, the alternative pathway (AP) complement protein Factor B (FB) along with C3 were positively modulated by CD40 ligation. Moreover, pharmacological inhibition of FB by proprietary GSK inhibitors, specifically cell-permeable small molecules was shown to suppress DC effector function. Subsequent work which assessed cell-derived anaphylatoxin generation was undertaken to validate the specificity of pharmacological inhibition. In conclusion, potential crosstalk mechanisms between the CD40- CD40L axis and FB may underscore DC activation profiles. Modulation of DC effector function may in turn influence iNKT activation at the iNKT-APC interface.
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