Brain microglia are characterized as uncommitted myeloid progenitors of immature dendritic cells (DC) or macrophages. Recently, it has been demonstrated that resident microglia can be skewed by astrocyte or microglia-produced cytokines to differentiate into immature DC.
Thereafter, various additional stimuli can induce differentiation into mature DC that have the potential to present (self) antigen and to prime naïve (autoreactive) T cells. We believe that these microglia-derived, mature DC play a crucial role in the pathogenesis of multiple sclerosis by inducing, shaping and/or sustaining autoimmune responses. However, they will do so only after having received the signals to mature in the brain itself. Key molecules in this process are the C-type lectin receptors (CLR) and Toll-like receptors (TLR). In addition, it is becoming increasingly clear that the combination of signals received via CLR and/or TLR is a decisive factor in determining what type of T cell response a DC will induce. We propose to identify which CLR and/or TLR are important for the maturation of microglia into DC and for the subsequent induction of an autoimmune response:
-Which CLR/TLR are expressed by different subsets of glia cells in vitro and in situ?
-Which (endogenous) factors influence the maturation of microglia into (im)mature DC and what are the roles of CLR/TLR in this process?
-How do different (infectious and non-infectious) insults lead to the induction of functionally distinct subsets of autoreactive T cells and what are the roles of different TLR in this process?
In vitro approaches, brought in by the fellow, form the heart of the project and will be incorporated in the extensive in vivo expertise present in the institute. The integrative approach will hopefully lead to new insights in how the brain plays a role in shaping the immune response against itself, allowing modulation in favour of inducing tolerance rather than the induction of an autoimmune response.
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