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Against invading microorganisms, vertebrates including mammals develop innate immune systems, which are activated by microbial components possessing conserved structures called pathogen associated molecular patterns (PAMPs); including bacterial cell wall components, and viral genomic DNA and RNA. PAMPs are recognized by pattern recognition receptors mainly expressing on immune responsive cells. Toll-like receptors (TLRS) are an example of pattern recognition receptors, and TLR family members are conserved among mammals. To date, 10 and 12 TLRs have been reported in human and mouse, respectively. Almost all TLRs have been shown to recognize PAMPs; TLR2 is the receptor for peptidoglycan and lipoprotein, including bacterial lipoprotein (BLP) and mycoplasmal lipoprotein (MALP-2). Especially, BLP and MALP-2 are reportedly recognized in the functional heterodimeric association of TLR2 with TLRl and TLR6, respectively. TLR4 is involved in the recognition of a gram-negative cell wall component, lipopolysaccharide (LPS). TLR5 is a receptor for flagellin, a component of bacterial flagella. TLR3 and TLR9 are receptors for double-stranded (ds) RNA and unmethylated CpG DNA, respectively. Although the natural ligand for TLR7 is yet to be identified, the receptor has been shown to recognize imidazoquid or its derivative, R- 848. Since they are utilized in the treatment of genital warts caused by human papilomavirus, the ligand for TLR7 seems to be a component of viruses. Thus, accumulating evidence clearly demonstrates that TLRs serve as pattern recognition receptors to detect invading microbes (Figure 1).

Work in recent years has shown an essential role for Toll-like receptors (TLRs) in the activation of innate and adaptive immunity in vertebrate animals. These germ-line encoded receptors, expressed on a diverse variety of cells and tissues, recognize conserved molecular products derived from various classes of pathogens, including Gram-positive and -negative bacteria, DNA and RNA viruses, fungi and protozoa. Ligand recognition induces a conserved host defense program, which includes production of inflammatory cytokines, upregulation of costimulatory molecules, and induction of antimicrobial defenses. Importantly, activation of dendritic cells by TLR ligands is necessary for their maturation and consequent ability to initiate adaptive immune responses. How responses are tailored by individual TLRs to contain specific classes of pathogens is not yet clear.

The Toll receptor families from insects and vertebrates have structural and evolutionary relationships and it was considered likely that they fulfilled similar functions in their respective organisms. Over the last two years, however, it has become clear that the way in which these receptors recognise pathogens in Drosophila and mammals is quite distinct. The completion of the genome sequences of Drosophila , human and mouse has revealed the presence of nine Toll receptors in the insect and probably ten or 11 in mammals. As shown in Fig. 1, with the exception of dToll9, the Drosophila Tolls are more closely related to each other than they are to the human Toll- like receptors (hTlrs). All Tolls are type 1 transmembrane receptors: they have blocks of a widespread structural motif, the leucine rich repeat in their ectodomains3, a single transmembrane spanning region and a cytoplasmic signalling module, the TollALlR identity region (TIR). The leucine rich repeat is found in many intracellular and extracellular proteins and has structural features that have the potential to evolve a wide range of protein binding specificities.s

The innate immune system senses pathogens largely through signals initiated by a collection of phylogenetically related proteins known as “Toll-like receptors” (TLRs), of which ten representatives are encoded in the human genome. The sensing role of the TLRs first came to light when one member of this family, TLR4, was shown to serve the detection of endotoxin (lipopolysaccharide; LPS) in mice. This discovery was based upon positional cloning of a spontaneous mutation affecting a locus known as Lps . The recognition specificities of other TLRs have since been established by reverse genetic methods. The understanding of the biochemical circuitry that maintains the innate capacity for immune recognition and response has loomed as the next hurdle in the field. A total of five adapter proteins with cytoplasmic domain homology to the TLRs are known to exist in mammals. These proteins are not entirely promiscuous in their interaction with TLRs, but rather, show preferential association with individual family members, giving a particular character to the signals that distinct micro-organisms initiate. The adaptive immune response is dependent upon upregulation of costimulatory molecules (UCM) such as CD80 and CD86. Very recently, it has been shown that this upregulation is dependent upon an adapter encoded by a locus known as Lps2 , known as Trif or Ticam-1, and upon type I interferon receptor signaling. LPS and dsRNA both signal via Trif, but dsRNA has an accessory pathway for UCM, that is independent of both Trif/Ticam-1 and the known dsRNA receptor, TLR3. Other key innate immunity genes have also been disclosed by germline mutagenesis, and are discussed in the present review.

NF-κB is a family of structurally related and evolutionarily conserved transcription factors. There are five NF-κB proteins in mammals: RelAIp65, RelB, c-Rel, NF-κB1 (p50 and its precursor p105), and NF-κB2 (p52 and its precursor p100); and three in flies: Dorsal, Dif, and Relish. All NFκB proteins contain a N-terminal 300 amino acid re1 homology domain, which is responsible for DNA binding, dimerization, and interaction with the inhibitors of NF-κB, the IκB family proteins. RelA, RelB, c-Rel, Dorsal, and Dif have a transcription activation domain at their C-termini, where p100, p105, and Relish contain ankyrin repeats, signature structures of IκB proteins. NF-κB proteins form hetero- or homodimers and are retained in the cytoplasm by IκBs. There are five IκB proteins in mammals: IκBα, IκBβ, IκBγ, IκBε, and Bcl-3; and one IκB protein in fly: Cactus. 1κBα and IκBβ share a tripartite organization: an N-terminal domain that is phosphorylated in response to signals, a central ankyrin repeat domain, and a C-terminal PEST domain that is involved in the basal turnover of the protein. All other IκB proteins have central ankyrin repeat domain, but differ from IκBα and IκBβ at their N- and C- terminal domains. IκB proteins form complexes with NF-κB dimers, with ankyrin repeats in direct contact with re1 homology domains. This interaction is essential to keep NF-κB dimers in the cytoplasm, thus physically sequestrating them from their transcriptional target.

Killer cell immunoglobulin-like receptors (KIR) are expressed on natural killer (NK) cells and on subpopulations of T cells, mostly CD8 cells, that have memory phenotype. KIR thus have the potential to contribute to both the innate immune response, through the action of NK cells, and the adaptive immune response, through the action of memory T cells. KIR were first defined functionally in the context of alloreactive human NK cells that showed specificity for polymorphic HLA class I determinants. Identified in this manner were inhibitory KIR with specificity for HLA-A, B and C determinants. Cloning of cDNA for these IUR led to the identification of additional KIR, some of which are activating receptors with HLA class I specificity and others - including both inhibitory and activating KIR - for which ligands have yet be defined (reviewed in [I]).

The term “NK receptors” has been applied to a growing number of cell surface receptors that were initially identified by their expression on NK cells. However, it is becoming increasingly obvious that few or none of the known “NK receptors” are completely restricted in expression to NK cells. For example, many of the inhibitory mouse Ly49 receptors were in fact originally cloned from T cell lines [1] , [2] , the NKR-PI [3] , [4] and CD94/NKG2A receptors are found on subsets of both human and mouse T cells [5] – [7] , and KIR have been identified on human T cells [8] , [9] . Typically, these “NK receptors” are present on effector or memory T cells, most frequently on γδ-TcR+ T cells or CD8+ T cells, and are rarely observed on naive resting T cells. Thus, the expression of “NK receptors” on T cells implies a role in adaptive, as well as innate, immunity.

Initially identified by their ability to kill tumor cells without prior sensitization of the host, natural killer (NK) cells are now known to provide a crucial initial defense against pathological organisms. In particular, they play a critical role during the early phases of infection (days 0 to 5) while specific immunity develops (reviewed in [1] ). Recent advances, however, indicate that NK cells specifically recognize virus-infected cells in a manner akin to their recognition of tumor cells, and also respond non-specifically to viral infections.

Dendritic cells (Dcs) are now widely understood to be perhaps the most efficient and critical of all antigen presenting cells. They are primarily responsible for acting as sentinels that detect and internalize foreign antigen in peripheral tissues and then conveying the antigen to lymphoid organs for presentation to T cells. Although B cells also exhibit an exquisite capacity for antigen presentation, they efficiently present only the single antigen recognized by the B cell receptor. DCs, on the other hand, can present a seemingly limitless array of complex protein, carbohydrate, and lipid antigens, and do so even if provided with only minute quantities. Moreover, DCs have a marked capacity to stimulate even immunologically naive T cells, and as such are increasingly thought to play a unique role in the initiation of all antigen-specific immune responses [1] .

Thymic stromal lymphopoietin (TSLP) is a novel interleukin (1L)-7-like cytokine [1] . The functional receptor for TSLP is a heterodimer consisting of the IL-7Rα chain and a common γ chain-like receptor called TSLP receptor (TSLPR) [1] , [2] . In humans, IL-7Rα chain and TSLPR mRNA are coexpressed on CDl lc+ immature myeloid dendritic cells (DCs), but not in other cell types [2] . Because human TSLP activates peripheral blood CDl lc+ immature DCs, we investigated how TSLP-activated DCs (TSLP-DCs) regulate human naive CD4+ T cell activation and differentiation [3] , [4] .