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.

The mechanisms by which the recognition of Toll-like receptor (TLR) ligands leads to host immunity remain poorly defined. It is now thought that to induce an effective immune response, microorganisms must stimulate complex sets of pattern-recognition receptors, both within and outside of the TLR family. The combined activation of these different receptors can result in complementary, synergistic or antagonistic effects that modulate innate and adaptive immunity. Therefore, a complete understanding of the role of TLRs in host resistance to infection requires 'decoding' of these multiple receptor interactions. This Review highlights recent advances in the newly emerging field of TLR cooperation and discusses their implications for the development of adjuvants and immunotherapies.

Pattern-recognition receptor

A receptor that recognizes unique structures that are shared by different microorganisms. Signalling through these receptors typically leads to the production of pro-inflammatory cytokines and chemokines and to the expression of co-stimulatory molecules by antigen-presenting cells. The expression of co-stimulatory molecules, together with the presentation of antigenic peptides, by antigen-presenting cells couples innate immune recognition of pathogens with the activation of adaptive immune responses.

Haemozoin

The crystalline product resulting from digestion of haemoglobin by the intraerythrocytic replicative stage of malaria parasites (Plasmodium spp.).

C-type lectins

Animal receptor proteins that bind carbohydrates in a calcium-dependent manner. The binding activity of C-type lectins is based on the structure of the carbohydrate-recognition domain (CRD), which is highly conserved between members of this family.

Cross-tolerance

Cross-tolerance is observed when the addition of a Toll-like receptor (TLR) ligand induces tolerance to subsequent challenge with the same stimulus used for priming and also to subsequent challenges with other stimuli that signal through one or more different TLRs.

Microarray analysis

A technique for measuring the transcription of genes. It involves hybridization of fluorescently labelled cDNA prepared from a cell or tissue of interest with glass slides or other surfaces dotted with thousands of oligonucleotides or cDNA, ideally representing all expressed genes in the species.

Crohn's disease

A form of chronic inflammatory bowel disease that can affect the entire gastrointestinal tract, but is most common in the colon and terminal ileum. It is characterized by transmural inflammation and granuloma formation, and it is thought to result from an abnormal T-cell-mediated immune response to commensal bacteria.

Caspases

A family of cytosolic proteases that contain a cysteine residue in the active site and that cleave their substrate after an aspartic-acid residue. They can be divided into pro-inflammatory caspases (caspase-1, -4, -5 and -11), which cleave and activate pro-inflammatory cytokines, and pro-apoptotic caspases, which cleave and activate pro-apoptotic substrates.

Contact hypersensitivity

The initial reaction that occurs after the first exposure to a 'sensitizer' hapten or antigen. This step requires dendritic-cell migration to lymph nodes to prime contact-antigen-specific T cells.