TLR-dependent T cell activation in autoimmunity

Key Points Toll-like receptors (TLRs) are members of the pattern recognition receptor (PRR) family. They sense pathogen-derived molecules termed pathogen-associated molecular patterns (PAMPs), as well as endogenous molecules termed damage-associated molecular patterns (DAMPs) that are released from dead and dying cells. Activation of TLR signalling pathways in innate immune cells, such as dendritic cells (DCs), drives adaptive immunity by enhancing the ability of DCs to act as antigen-presenting cells and promoting the production of pro-inflammatory cytokines that direct the induction of different T cell subtypes. Autoimmune diseases can develop as a result of a breakdown in immune tolerance that leads to the activation of autoantigen-specific T cells. Self-reactive T cells that secrete interleukin-17 (T H 17 cells), interferon-γ (T H 1 cells) or both cytokines mediate inflammatory pathology in many autoimmune diseases. Infectious pathogens and the gut microbiota have been implicated in precipitating or exacerbating autoimmune diseases in humans. Studies in mouse models and with tissues from patients with autoimmune diseases have suggested that PAMPs may promote innate and consequently adaptive immune responses that promote inflammation and tissue damage. The release of endogenous DAMPs from host cells that have been killed as a result of damage or infection with pathogens can activate innate immune responses, driving sterile inflammation that initiates or exacerbates pathology in autoimmune diseases. Inhibition of agonist binding to TLRs or downstream signalling pathways is a promising approach for the development of therapies for inflammatory and autoimmune diseases. 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 adj