CORE Metadata, citation and similar papers at core.ac.uk Provided by Elsevier - Publisher Connector Immunity Perspective Approaching the Asymptote: 20 Years Later Ruslan Medzhitov1,* 1Howard Hughes Medical Institute and Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510, USA *Correspondence: [email protected] DOI 10.1016/j.immuni.2009.06.004 The pattern recognition theory proposed by the late Charles Janeway, Jr. 20 years ago provided a conceptual framework for our current understanding of the innate immune recognition and its role in the activation of adaptive immunity. Discovery of several families of pattern recognition receptors and their roles in mamma- lian immunity provided experimental support for the Janeway’s theory. In addition to pattern recognition, there are other forms of innate immune sensing, which presumably work in specific combinations depending on the pathogen class and the type of the immune response they elicit. Here, the development of the Jane- way’s theory is discussed in the context of the advances made in field of innate immune recognition over the past two decades. ‘‘It is amateurs who have one big bright beautiful idea that respond to any antigens they may encounter because these by they can never abandon. Professionals know that they definition would be nonself. The concept was later modified by have to produce theory after theory before they are likely the two-signal model of Bretscher and Cohn (Bretscher and to hit the jackpot.’’ Francis Crick, What Mad Pursuit: A Cohn, 1970) and by the costimulatory model suggested by Personal View of Scientific Discovery (1988) Lafferty and Cunningham (Lafferty and Cunningham, 1975). The first experimental evidence for the two-signal requirement This year marks the 20th anniversary of a publication (Janeway, for T cell activation was later provided by Marc Jenkins and 1989) that in many ways revolutionized our understanding of Ronald Schwartz (Jenkins and Schwartz, 1987), although the the immune system. As part of the proceedings of the Cold nature of the second signal remained unknown for a few more Spring Harbor Symposium on Immune Recognition, the paper years. Importantly, however, in an unrelated line of studies, An- authored by the late Charles A. Janeway, Jr. was not a standard tonio Coutinho and Go¨ ran Mo¨ ller discovered the distinct roles peer-reviewed publication. In fact, Charlie used to refer to it as of antigen-specific and polyclonal signals in B cell activation ‘‘the best paper I’ve never published.’’ According to the Francis (Coutinho and Moller, 1974). The polyclonal (or mitogenic) signal Crick’s quotation above, Charlie was definitely a ‘‘professional’’ in their experiments was provided by lipopolysaccharide (LPS), who had many ideas and who hit more than one jackpot. The and thus their studies made one of the first critical connections pattern recognition theory was the biggest one. In addition to between antigen-specific receptor and nonclonal microbial suggesting a general principle of innate immune recognition, it receptors in activation of B cell responses. Other studies estab- provided a conceptual framework for the integration of the two lished adjuvant properties of LPS (Condie et al., 1955; Skidmore types of immunity—innate and acquired. It also suggested et al., 1976). In the meantime, Ralph Steinman, working in Zanvil a new set of ideas that explained the initiation of the immune Cohn’s group, discovered dendritic cells and characterized their responses, the mechanism of adjuvant effects, and the evolution unique immunostimulatory activity (Steinman and Cohn, 1973, of different forms of immune recognition. Collectively, these 1974). A critical connection between the initiation of T and B ideas provided guiding principles for our current understanding cell responses was provided by the discovery of antigen-specific of the functioning of the innate immune system and its connec- T and B cell interactions by Antonio Lanzavecchia (Lanzavec- tion with adaptive immunity. chia, 1985). Together, these and many other pioneering discov- eries, including analyses of the specificity of antibody responses Early Studies on the Initiation of Innate and Adaptive by Karl Landsteiner (Landsteiner, 1945), provided the essential Immunity background for future analyses of how the adaptive immune In the late 80s and early 90s, immunologists focused much of response is initiated. their attention on the mechanisms of adaptive immune recogni- In parallel, fundamental advances were being made in studies tion, including the structure and function of the antigen recep- of the innate host defense mechanisms. During the 1970s, anal- tors, the mechanisms of MHC restriction, and lymphocyte devel- yses of antimicrobial mechanisms of neutrophils and macro- opment and activation. However, little was known about the phages, particularly by Zanvil Cohn and his many pupils and requirements for the activation of adaptive immune responses. collaborators, including James Hirsch, Seymour Klebanoff, Carl Although the question of self-nonself discrimination has preoc- Nathan, Siamon Gordon, Ralph Steinman, Alan Aderem, Ira cupied the minds of immunologists for decades, the solution Mellman, Bill Muller, Gilla Kaplan, and many others, had estab- was thought to be largely provided by the pioneering works of lished many basic principles of macrophage and neutrophil func- Lederberg, Burnet, and Medawar (Billingham et al., 1953; tions, including phagocytic process, degranulation, secretory Burnet, 1959; Lederberg, 1959). The central idea at the time function, arachidonic acid metabolism, and oxygen-dependent was that the removal or inactivation of autoreactive clones during and -independent bacteriocidal functions (reviewed in Steinman lymphocyte development allowed the remaining lymphocytes to and Moberg, 1994). Many of these functions were found to be 766 Immunity 30, June 19, 2009 ª2009 Elsevier Inc. Immunity Perspective inducible in macrophages by microbial stimuli, including LPS, of immune recognition must be evolutionarily related to the Bacillus Calmette-Gue´ rin (BCG), and zymosan. Thus, the idea of immune systems of invertebrates, which lack adaptive immunity. microbial stimulation of innate effector functions was well appre- Finally, most adjuvants were suggested to work in part by ciated by that time. In addition, the discovery of antimicrobial mimicking microbial infections, by triggering the receptors of peptides by Hans Boman revealed a powerful microbicidal the innate immune system and inducing costimulatory signals, system, which is now known to be used by most and perhaps thus ‘‘tricking’’ the adaptive immune system into action. These all organisms for antimicrobial defense. In the field of antiviral and other ideas provided an elegant explanation of many funda- immunity, the crucial advances were the discovery of type I inter- mental aspects of the functioning of the immune system. feron (IFN) activity (Isaacs and Lindenmann, 1957; Isaacs et al., Remarkably, all of them turned out to be fundamentally correct. 1957; Nagano and Kojima, 1958), cloning of the first type I IFN Nevertheless, the new theory did not seem to attract a lot of gene (IFN-b) by Tadatsugu Taniguchi (Taniguchi et al., 1980), attention at first. The situation started to change about a decade and the isolation of the IFN-a gene by Shigekazu Nagata and later, when new studies began elucidating the pathways of Charles Weismann (Nagata et al., 1980). Importantly, type I IFNs innate immune recognition. were known to be inducible by poly IC, presumably because it mimics viral dsRNA—another important target of innate immune Toll-like Receptors recognition. Finally, characterization of two mouse strains defi- By the mid-90s, several receptors involved in innate immune cient in LPS responsiveness, C3H/HeJ (Heppner and Weiss, recognition were already known. These included CD14, a compo- 1965) and C57BL/10Cr (Coutinho et al., 1977), and demonstration nent of the LPS receptor complex (Wright et al., 1990); Mannan- of their susceptibility to a bacterial infection (O’Brien et al., 1980) binding lectin (MBL), an activator of the lectin pathway of comple- demonstrated that LPS recognition plays a critical role in host ment (Takahashi et al., 2006); macrophage mannose receptor defense against at least some Gram-negative pathogens. (Stahl and Ezekowitz, 1998); and MARCO, a member of the scav- The two lines of study briefly outlined above were developing enger receptor family (Elomaa et al., 1995). MBL was particularly largely independently of each other, as reflected in the way the well characterized in terms of its specificity and function. Its role innate and adaptive immune systems were covered in textbooks. in complement activation and microbial opsonization was remi- The critical role of innate immune recognition in the control of niscent of immunoglobulins, suggesting that MBL functioned as adaptive immunity was not well appreciated and a new concep- a nonclonal version of antibodies. To emphasize this point, Alan tual framework was clearly needed to integrate innate and adap- Ezekowitz referred to MBL as ‘‘ante-antibody,’’ highlighting the tive immune recognition to explain the fundamental properties of evolutionary ancestry of the former (Ezekowitz, 1991). However mammalian immunity. MBL, as well as pentraxins, although known at the time to func- tion as pattern recognition molecules, were not the type of recep- Janeway’s Hypothesis tors that would be expected to control