Yin–Yang regulation of autoimmunity by DCs

The key function of the immune system is to promptly signal danger by invading pathogens, while ignoring self-antigens, in which the immune cells are bathed. Autoreactive T cells, which have escaped thymic selection, are present in the normal repertoire and can be activated relatively easily and many pathogens contain lookalike determinants (mimicry epitopes) of self-antigens. To prevent induction of autoimmunity, the immune system uses a highly effective control mechanism, which efficiently discriminates between self and non-self. Peripheral tolerance to self-antigens is maintained by immature dendritic cells (iDCs), whereas mature DCs can activate autoreactive T cells. A homeostatic control mechanism operating through the balance between C-type lectin receptors (CLRs) and Toll-like receptors (TLRs) on DCs will be discussed. DC maturation induced by TLR binding of pathogen-associated molecular patterns (PAMPs) can be antagonized by CLR stimulation by specific carbohydrate structures on self-antigens and pathogens. We hypothesize that disturbed glycosylation of self-antigens might set the stage for autoimmunity by weakening the capacity of CLRs to buffer ‘danger signals’ through TLRs.