Discovery of Drosophila Toll and its eight homologs counity include the principle of somatic recombination to pled with identification of homologous mammalian Toll- generate the diverse T cell and B cell receptor repertoire like receptors (TLRs) that discriminate “self” from pathoand the ability to form memory responses upon pathogen-derived ligands (also termed pathogen associated gen exposure. molecular patterns [PAMPs])(Hoffmann et al., 1999) has TLR-Initiated Signaling rejuvenated research on “innate immunity.” Today we As far as it is known, all TLRs activate innate immune have come to realize that, for the recognition of patho- cells via the Toll/interleukin-1 receptor signal pathway gens, plants and insects have relied for millions of years(Hoffmann et al., 1999; Aderem and Ulevitch, 2000)(see upon a system of receptors that share a characteristic Figure 1). As a first cytosolic event, the adaptor molecule cytoplasmatic domain now termed TIR (Toll/inter- MyD88 is recruited to the receptor complex, followed by leukin-1 receptor domain). Amazingly, the TIR domain engagement of IL-1 receptor associated kinases (IRAKs) has remained conserved, and it functions in antipatho- and the adaptor molecule TRAF6. Oligomerization of gen responses in plants, insects, and mammalians alike. TRAF6 leads to activation of downstream kinases like In mammals, 10 Toll homologs (TLRs) have been identi- the stress kinases c-Jun N-terminal kinase (JNK), p38, fied so far, all of which appear to be type I integral and IκB kinase (IKK) complex. This results in the activamembrane proteins with extracellular leucine-rich re- tion of transcription factors like AP-1 and NF-κB. Repeats (LRRs) and cytoplasmatic TIRs (Hoffmann et al., cruitment of MyD88 seems to be an essential step since 1999; Aderem and Ulevitch, 2000). It has also become MyD88-deficient cells exhibit severe impairment of inclear that innate immune cells such as macrophages nate immune responses to PAMPs. Interestingly, upon and dendritic cells (DCs) heavily impact on adaptive phagocytosis of particles including living bacteria, TLRs immune responses; innate immune cells control as anti- become recruited to phagosomes, presumably to screen gen-presenting cells (APCs) whether T cells respond at the contents for their ligands and subsequently to trigger all and whether emanating adaptive T cell responses signaling via MyD88 (Ozinsky et al., 2000). become polarized toward Th1 or Th2 (Aderem and Ule- The idea that PAMPs activated TLRs uniformly and vitch, 2000). Accordingly, we now argue that innate im- exclusively initiate signaling via the TLR/IL-1 receptor munity was not only first but also effectively instructs pathway may turn out to be too simplistic. For example, subsequent adaptive responses to pathogens. the cytoplasmatic TIRs of distinct TLRs appear not to In flies, Toll is involved in antifungal responses, and be functionally equivalent, since TLR1, TLR2, and TLR6 one of its homologs, 18-wheeler, confers respon- are believed to require heterodimenerization to induce siveness to Gram-negative bacteria (Hoffmann et al., TNF-α production in macrophages, while TLR4 func-1999). In a seminal report, Janeway and colleagues iden- tions on its own (Hajjar et al., 2001; Ozinsky et al., 2000). tified the first human homolog of Drosophila Toll (Med- Interestingly, TLR2 appears to activate a signaling cascade composed of the Rho GTPase Rac1, the phosphazhitov et al., 1997), and subsequent positional cloning tidylinositol-3 kinase (PI3K), and Akt that targets nuclear revealed that it encodes a signal transduction and re-NF-κB transactivation independently of IκBα degradaceptor component …