Modulation of tlr signalling pathways in pursuit of therapy

The innate immune system provides the first line of defense against infection. Cells of the innate immune system recognize and are activated by highly conserved structures expressed by large group of microorganisms called pathogen-associated molecular patterns (PAMPs). A limited number of germline-encoded pattern recognition receptors (PRRs) are involved either in recognition (scavenger receptors, C-type lectins) or in cell activation (Toll-like receptors or TLR, helicases and NOD molecules). TLRs play a pivotal role in cell activation in response to PAMPs. TLR are type I transmembrane proteins that are expressed not only by innate immune cells but also lymphocytes comprising the adaptive immune system and non immune cells. In all the cell types analyzed, TLR agonists, alone or in combination with costimulatory molecules, induce cell activation. The ability of different cell types to respond to TLR agonists is related to the pattern of expression of the TLRs and its regulation as well as their intracellular localization. Ligation of TLR controls innate and adaptive immune responses by inducing synthesis of pro- as well as anti-inflammatory cytokines and activation of effector as well as regulatory lymphocytes. TLRs are therefore considered as major targets for the development of vaccine adjuvants, but also of new immunotherapies. The potential of TLR ligands as a novel class of pharmaceuticals for the prevention or treatment of allergic disorders, the enhancement of anti-tumour-immune responses and the therapeutical modulation of infectious diseases will be discussed.