In 1989, Charles Jeneway published it classical paper discussing inate immunity and establishes the fact that recognition of pathogen is done by germline-encoded receptors and not the recombinant antigen receptors (Janeway, 1989) He establishes the role of co stimulatory molecules or signals responsible for T cell activation. After extensive research of almost 20 years we have identified that co- stimulatory signal named as Toll receptor and its pathway. Surprisingly people working with different model system recognize that Toll receptor was not only responsible for human innate immunity but also found in wide range of living systems starting from earthworm to plants. Initially Toll receptor was recognized for its role in innate immunity but later on many unique role of toll was appeared in different model system like In drosophila where Toll have key roles in development. Investigation of Toll receptors and pathway related or activated by this receptor open ups new era of innate immunity and give us insight in to evolutionary conservation.
Toll like receptors (TLR) are PRRs (pattern recognition receptor) having unique and essential role in innate immunity. It comprises of family of type I transmembrane receptors characterized by an extracellular leucine rich repeat domain and intracellular Toll/IL-1 receptor (TIR) domain. LRR founds in diverse set of proteins having role in ligand recognition and signal transduction (Ruslan Medzhitov, 2001). The signature sequence of LRR is L(X2) LXL(X2) NXL(X2) L(X7) L(X2). Where X2 is any amino acids. The TIR domain of Toll receptor is conserved protein-protein interaction module found in different transmembrane and cytoplasmic proteins in animals and plants. Interestingly, most of these TIR associated proteins in animals and plants have a role in host defense.
Figure:1 Schematic of Toll likes receptor (TLR) (www.icampus.ucl.ac.be)
TLR in mammalian Immunity:
In mammalian species there are at least 10 TLR, and having distinct role in innate immunity. There are almost dozens of ligand for TLR were identified and many more yet to be established. TOL ligand are quite diverse in nature but having some common characteristics like most of TLR ligands are conserved microbial products (PAMPs), TLR recognize different structurally unrelated ligand and some TLR requires accessory proteins to recognize its ligand . Fig 2 shows different ligand molecules recognized by mammalian TLRs.
(Ruslan Medzhitov Nature Reviews Immunology 1, 135-145 November 2001)
Figure: 2 Ligand specification of TLR
Activation of signal transduction pathway by TLR leads to expression of several genes have key role in host defense. For example TLR activated signaling pathway activates expression of cytokines, chemokines, MHC and various co stimulatory molecules (Ruslan Medzhitov, 2001). Initially it was proposed that all TLR have similar signaling cascade but growing evidences indicates that even though there are conserved signaling molecules in TLR pathway, there are differences among different types of TLR mediated