Early induced immune responses : regulation of dendritic cell and NK cell functions

Abstract: The evolution of the advanced vertebrate adaptive immune system has required co-evolution of sophisticated immune regulating systems that determine immune class of cytokines, antibodies as well as effector mechanisms used by killer cells. The co-ordination of these responses are likely to be carried out by dendritic cells (DC) under the influence of the tissue cells and innate immune cells resident in the tissue from where the DC originates. To achieve its job, the DC relies on ancient mechanisms of antigen uptake, phagocytosis and pinocytosis, driven by actin cytoskeleton rearrangements. The regulation of this is studied in paper I. The same actin cytoskeleton system is involved in the motility and chemotaxis that guides the DC to the lymphnode where it attracts naïve T cells and activates the ones that are specific for any antigen it displays. The DC has the ability, via cell surface molecules and cytokines, to determine the immune class of the activated T cells. One signal that influences the DCs capability to produce immune class switching cytokines is PGE2. It regulates the DC response to microbial stimulus in a manner dependent on cAMP signalling. cAMP signalling augments the production of IL-10 and inhibits the production of TNFalpha OBS. and IL-12p7O. This phenomena is studied in paper II. Before the adaptive immune system is activated and the effector cells has expanded enough, the infected tissue and the innate immune system has to deal with the infection. One of the cells that combat virus infection, and that also may have the capability to eliminate tumor cells, is the naturall killer cell (NK) cell. A balance between inhibiting and activating signals regulates NK cell effector functions. The killer cell inhibitory receptors recognize self-MHC molecules. If MHC gets down regulated (decreased inhibiting signals) or if activating stress molecules are up regulated (increased activating signals) the result is triggering of NK cell effector function. MHC can be down regulated due to virus infection and it is also often down regulated on tumor cells. NK cells can be activated by MHC like activating ligands that are stress regulated using the receptor NKG2D. NK cells produce high amounts of IFNgamma OBS upon activation and use both the perforin/granzyme pathway, NK lysin peptides as well as death receptor ligands to eliminate its targets. The use of and regulation of deathreceptor mediated killing is studied in papers III and IV.