Cooperation of Toll-like receptor signals in innate immune defence

Toll-like receptor (TLR)-mediated recognition of pathogens is now thought to have a crucial role in innate immune defence, as well as in adaptive immunity. Nevertheless, the triggering of a single TLR is rarely sufficient to mediate these functions in response to microorganisms and so other members of the TLR family, as well as pattern-recognition receptors belonging to other families, must cooperate to stimulate effective host resistance.In vitro studies have indicated that stimulation with multiple ligands each targeting different TLRs leads to marked synergy in the activation of antigen-presenting cells (such as dendritic cells and macrophages). Such synergy is particularly notable when interleukin-12 (IL-12) is used as a 'read-out' of TLR stimulation.Systematic analyses of the effects of different combinations of TLR ligands have indicated that the strongest synergies occur between ligands that trigger distinct signalling pathways (such as the MyD88- and TRIF-dependent signalling pathways).The combined effects of ligation of multiple TLRs are potent and sufficient to stimulate the production of high levels of IL-12 without the need for secondary signals from T cells or enhancement by paracrine cytokines such as interferon-γ.In vivo studies confirm that in many models of infectious disease, deficiencies of multiple TLRs cause a greater reduction in host resistance than single TLR deficiencies. These effects are nevertheless complex, often involving multiple effector cells and responses, as well as negative and positive effects of TLR ligation for the host.The investigation of pathways of TLR cooperation in the response to infection should lead to a better understanding of the mechanisms of host resistance and provide a basis for the development of more effective adjuvants and immunotherapeutic regimens.