View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Leading Edge BenchMark Bridging Innate and Adaptive Immunity William E. Paul1,* 1Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1892, USA *Correspondence: [email protected] DOI 10.1016/j.cell.2011.11.036 The Nobel Prize in Physiology or Medicine for 2011 to Jules Hoffmann, Bruce Beutler, and the late Ralph Steinman recognizes accomplishments in understanding and unifying the two strands of immunology, the evolutionarily ancient innate immune response and modern adaptive immunity. Among the 15 Nobel prizes given for siveness. The celebration of immunolo- the eponymous complete Freund’s adju- discoveries in immunology, including the gists everywhere in response to this vant, consisting of killed Mycobacteria very first, the 2011 prize can be best well-deserved prize is tempered with tuberculosis organisms in a water-in-oil compared to the 1908 prize, shared by sadness, with Ralph Steinman having emulsion. two giants of modern science, Paul died on the Friday preceding the Monday Although this need to use adjuvants to Ehrlich and Ilya Metchnikoff. In awarding announcement of the award. obtain a robust immune response to that prize, the Nobel committee attemp- protein antigens was widely appreciated, ted to grapple with the divide that had Exploring Immunology’s ‘‘Dirty it was papered over as immunologists’ already arisen in the then infant science Little Secret’’ ‘‘dirty little secret.’’ In a remarkably of immunology, using the simple award The narrative underlying the award to prescient and influential lecture at the statement, ‘‘in recognition of their work Hoffmann and Beutler, representing opening of the 1989 Cold Spring Harbor on immunity.’’ innate immunity, and Steinman, very Symposium on Quantitative Biology In fact, Ehrlich (Ehrlich, 1900) and much on the interface between innate (Janeway, 1989), Charles Janeway moti- Metchnikoff (Metchnikoff, 1891) were the and adaptive responses, begins with two vated immunologists everywhere to think champions of two divergent views of how independent themes. Although Stein- about this problem. Janeway argued the body protects itself against foreign man’s key discovery was made earlier, I that the immune system required not invaders. The one concentrated on the start with a description of the reawaken- only an antigen/receptor interaction to exquisitely specific adaptive immune re- ing of the interest of immunologists in initiate a response, but a parallel recog- sponse that exhibited the features of innate immunity. It would be presump- nition of structures that pathogens ex- learning and recall and was the basis tuous to imply that the study of the innate pressed (pathogen-associated molecular of the remarkably successful procedure immune system had ceased in the years patterns [PAMPs]), which would be rec- of vaccination, the only medical interven- after Metchnikoff’s work. But there can ognized by receptors broadly expressed tion that has eradicated diseases (two so be little doubt that, following the proposal by cells of the immune and inflammatory far, smallpox in humans and rinderpest by David Talmage (Talmage, 1957) and systems (pattern recognition receptors in cattle). By contrast, the adherents of by Macfarlane Burnet (Burnet, 1957)of [PRRs]). He posited that these interac- innate immunity emphasized the near the clonal selection theory of immunity, tions stimulated cellular events that were universal capacity of multicellular life the attention of the majority of immunolo- essential for the activation, expansion, forms, including plants, to protect them- gists was riveted on the adaptive system, and differentiation of T and B lympho- selves against foreign invaders with ex- and most of the other Nobel prizes in cytes that would eventually result in elim- tremely effective tools to eliminate or immunology (although not all) were for ination or control of the pathogen. control the invader utilizing the inflamma- advances in understanding adaptive Janeway’s proposal of a microbial tory system. immunity. sensor eliciting an innate immune re- We return to this divide in 2011, but not Yet despite this great attention, all was sponse that was subsequently interpreted in the stark terms that separated Ehrlich not well in the understanding of how by lymphocytes, the key cells of the adap- and Metchnikoff. For the work of the adaptive immune responses were initi- tive immune system, as ‘‘permission’’ to new Nobel Laureates—Jules Hoffmann ated. A great challenge was to determine mount a response when they recognized and Bruce Beutler, ‘‘for their discoveries why the simple introduction of an anti- an antigenic substance was enormously concerning the activation of innate immu- genic protein led to a very weak response influential. Although there was ‘‘no flesh nity’’ and the late Ralph Steinman, ‘‘for or tolerance unless an adjuvant was on the bones,’’ as I will recount later, the his discovery of the dendritic cell and its co-injected to enhance the response. cell that interpreted the innate response role in adaptive immunity’’ —to a very Perhaps the most famous of these was to the adaptive system, the dendritic large degree represents the merging of introduced by my predecessor twice cell, had already been discovered by the two strands and the recognition of removed as chief of the NIAID Laboratory Ralph Steinman. The key step, the finding the fundamental unity of immune respon- of Immunology, Jules Freund, known for of molecular entities that represented the 1212 Cell 147, December 9, 2011 ª2011 Elsevier Inc. PRRs and the PAMPs, was what truly that activated the system in humans, C57BL/10ScCr/ C57BL/10ScSn, one of galvanized the immunological community there is an important intermediate finding. which could respond to LPS and one and led to a revolution in how we under- Charles Janeway and his then postdoc- that failed to respond. To type these stand host-pathogen interactions. toral fellow Ruslan Medzhitov, working at mice, he made use of the capacity of In 1996, Jules Hoffmann, with his Yale University, immediately recognized macrophages from wild-type mice to pro- colleagues Lemaitre, Nicolas, Michaut, that the finding by Hoffmann in flies duce TNFa upon stimulation with LPS and Reichhart, working at the Institut de provided a powerful tool that might aid and the failure of macrophages from Biologie Mole´ culaire et Cellulaire in Stras- in determining the nature of microbial mutant mice to do so. Using a positional bourg, reported that, in Drosophila, an sensors in humans. Medzhitov and Jane- cloning effort over a period of several intact gene cassette consisting of spa¨ t- way scanned the expressed sequence years, he reported in 1998 (Poltorak zle/Toll/cactus/dorsal was essential if tag database and found a transcript that et al., 1998) that the gene that was mutant the fly was to mount a potent antifungal encoded a homolog of Drosophila Toll. in the LPS unresponsive mice was Tlr4, response (Lemaitre et al., 1996). It had They wished to determine whether this which coded for the very TLR that Medz- already been shown that fly resistance human Toll homolog initiated activation hitov and Janeway had shown could acti- to certain bacterial infections was con- of NF-kB, as Drosophila Toll did, and led vate NF-kB and cause proinflammatory trolled by the gene designated immune to the release of key proinflammatory cytokine production when crosslinked. deficiency (imd), but it was clear that cytokines. Because Medzhitov and Jane- This indicated that LPS was a direct or many other infections were not controlled way did not know the ligand for their indirect ligand for TLR4 and showed by the action of imd alone. Hoffmann and ‘‘Toll-like receptor’’ (TLR), they prepared that precisely the type of molecule that his colleagues became interested in the a molecular chimera in which the extra- would fit into Janeway’s postulated set system that activated the morphogen cellular domain of the T cell differentiation of PAMPs could activate production of dorsal because its signaling pathway, marker CD4 was linked to the cytosolic potent mediators of inflammation. initiated by Toll, showed a striking domain of the TLR that they had identi- Of course, as is true of all seminal similarity to components of a key activator fied. They expressed this chimera in a discoveries, what I have described is of vertebrate immune/inflammatory re- human monocyte cell line and showed merely the thin edge of the wedge. The sponses, the interleukin 1 (IL-1)/NF-kB that, when crosslinked with an anti-CD4 study of the TLRs as microbial sensors signaling pathway. The cytosolic portion antibody, NF-kB was activated and a has truly burgeoned, enlisting a legion of of Toll exhibits homology to the compa- series of proinflammatory cytokines extremely gifted investigators who have rable region of the IL-1 receptor, and were produced, including IL-1, IL-6, and identified ligands for each of the TLRs. cactus is homologous to a key regulator IL-8. This work, published in 1997 (Medz- Of these, Shizuo Akira of Osaka University of NF-kB activation, I-kB, and likewise hitov et al., 1997), established that is the generally acknowledged leader, dorsal to NF-kB. Hoffmann and his humans had at least one Toll homolog combining gene knockout technology colleagues showed that the spa¨ tzle/Toll/ (this proved to be TLR4) and that its and elegant biochemistry to determine cactus/dorsal signaling pathway con- signaling properties resembled those of which of the microbial products activate trols the production of the antifungal Drosophila Toll and of human IL-1. This which TLRs. The ligands include double- peptide drosomycin and that flies with still left unknown what TLRs recognized stranded RNA, single-stranded RNA, mutations in this pathway have a dramatic and thus whether the TLRs were the CpG oligodeoxynucleotides, bacterial reduction of survival following fungal microbial sensors/PRRs that Janeway flagellin, lipopeptides, and zymosan, a infection.