TLR-dependent T cell activation in autoimmunity

Infection, tissue injury and alterations in the composition of the microbiota have been implicated in the initiation of autoimmune diseases. In this Review article, Kingston Mills discusses how Toll-like receptor (TLR) signalling downstream of all these events can regulate the function of autoreactive T cells both directly and indirectly (through the activation of innate immune cells), and comments on the therapeutic implications of TLR targeting. Autoimmune disease can develop as a result of a breakdown in immunological tolerance, leading to the activation of self-reactive T cells. There is an established link between infection and human autoimmune diseases. Furthermore, experimental autoimmune diseases can be induced by autoantigens that are administered together with complete Freund's adjuvant, which contains killed Mycobacterium tuberculosis; in some cases, these bacteria can be replaced by individual pathogen-associated molecular patterns (PAMPs). Exogenous PAMPs and endogenous danger signals from necrotic cells bind to pattern recognition receptors (including Toll-like receptors) and activate signalling pathways in innate immune cells and in T cells. This leads to pro-inflammatory cytokine production and T cell activation, which are now considered to be major factors in the development of autoimmunity.