Ruslan Medzhitov

A human homologue of the Drosophila Toll protein signals activation of adaptive immunity

Induction of the adaptive immune response depends on the expression of co-stimulatory molecules and cytokines by antigen-presenting cells. The mechanisms that control the initial induction of these signals upon infection are poorly understood. It has been proposed that their expression is controlled by the non-clonal, or innate, component of immunity that preceded in evolution the development of an adaptive immune system in vertebrates. We report here the cloning and characterization of a human homologue of the Drosophila toll protein (Toll) which has been shown to induce the innate immune response in adult Drosophila. Like Drosophila Toll, human Toll is a type I transmembrane protein with an extracellular domain consisting of a leucine-rich repeat (LRR) domain, and a cytoplasmic domain homologous to the cytoplasmic domain of the human interleukin (IL)-1 receptor. Both Drosophila Toll and the IL-1 receptor are known to signal through the NF-κB pathway. We show that a constitutively active mutant of human Toll transfected into human cell lines can induce the activation of NF-κB and the expression of NF-κB-controlled genes for the inflammatory cytokines IL-1, IL-6 and IL-8, as well as the expression of the co-stimulatory molecule B7.1, which is required for the activation of naive T cells.

Toll-like receptors and innate immunity

Toll-like receptors have a crucial role in the detection of microbial infection in mammals and insects. In mammals, these receptors have evolved to recognize conserved products unique to microbial metabolism. This specificity allows the Toll proteins to detect the presence of infection and to induce activation of inflammatory and antimicrobial innate immune responses. Recognition of microbial products by Toll-like receptors expressed on dendritic cells triggers functional maturation of dendritic cells and leads to initiation of antigen-specific adaptive immune responses.

Toll-like receptor control of the adaptive immune responses

Recognition of microbial infection and initiation of host defense responses is controlled by multiple mechanisms. Toll-like receptors (TLRs) have recently emerged as a key component of the innate immune system that detect microbial infection and trigger antimicrobial host defense responses. TLRs activate multiple steps in the inflammatory reactions that help to eliminate the invading pathogens and coordinate systemic defenses. In addition, TLRs control multiple dendritic cell functions and activate signals that are critically involved in the initiation of adaptive immune responses. Recent studies have provided important clues about the mechanisms of TLR-mediated control of adaptive immunity orchestrated by dendritic cell populations in distinct anatomical locations.

Recognition of Commensal Microflora by Toll-Like Receptors Is Required for Intestinal Homeostasis

Toll-like receptors (TLRs) play a crucial role in host defense against microbial infection. The microbial ligands recognized by TLRs are not unique to pathogens, however, and are produced by both pathogenic and commensal microorganisms. It is thought that an inflammatory response to commensal bacteria is avoided due to sequestration of microflora by surface epithelia. Here, we show that commensal bacteria are recognized by TLRs under normal steady-state conditions, and this interaction plays a crucial role in the maintenance of intestinal epithelial homeostasis. Furthermore, we find that activation of TLRs by commensal microflora is critical for the protection against gut injury and associated mortality. These findings reveal a novel function of TLRs-control of intestinal epithelial homeostasis and protection from injury-and provide a new perspective on the evolution of host-microbial interactions.

Origin and physiological roles of inflammation

Inflammation underlies a wide variety of physiological and pathological processes. Although the pathological aspects of many types of inflammation are well appreciated, their physiological functions are mostly unknown. The classic instigators of inflammation — infection and tissue injury — are at one end of a large range of adverse conditions that induce inflammation, and they trigger the recruitment of leukocytes and plasma proteins to the affected tissue site. Tissue stress or malfunction similarly induces an adaptive response, which is referred to here as para-inflammation. This response relies mainly on tissue-resident macrophages and is intermediate between the basal homeostatic state and a classic inflammatory response. Para-inflammation is probably responsible for the chronic inflammatory conditions that are associated with modern human diseases.

Innate Immunity: The Virtues of a Nonclonal System of Recognition

One of the predictions of the clonal selection theory was the ability of mature peripheral lymphocytes to discriminate between self and nonself. All self-reactive lymphocytes were thought to be deleted during maturation, and any molecule presented to the mature lymphocytes would be regarded as nonself and should therefore induce an adaptive immune response. Indeed, early experiments with model antigens, such as simple chemicals conjugated to self serum proteins and injected with adjuvants showed that responses to such antigens were the norm rather than the exception. However, if unmodified self antigens, and even nonself proteins, were administered alone in the absence of adjuvant, they gave rise to tolerance rather than an immune response. Immune responses specific even for self antigens could be induced, however, if the self antigen was mixed with adjuvants.Although adjuvants have a long history, so far they have only been defined operationally as any substance that increases the immunogenicity of admixed antigens. The reason for the failure of pure antigens to induce immune response is now known—the antigens used in these studies failed to induce the costimulatory signal necessary for the activation of lymphocytes. Accordingly, the mechanism of adjuvant activity has been proposed to be due to the induction of costimulatory signals by microbial constituents carrying PAMPs that are routinely mixed in adjuvants (Janeway 1989xCold Spring Harbor Symp. Janeway, C.A. Jr. Quant. Biol. 1989; 54: 1–13Crossref | PubMedSee all ReferencesJaneway 1989). Recognition of these PAMPs by PRRs is suggested to induce the signals necessary for lymphocyte activation (such as B7) and differentiation (effector cytokines; see above). In other words, adjuvants induce the innate immune system to produce the signals that are required for activation of an adaptive immune response. While adjuvants are potent immunostimulators, most of them cannot be used in the clinic because of unwanted side effects, and much adjuvant research has been directed toward identification of the active components of the adjuvants and their subsequent modification to minimize side effects (for review, seeAudibert and Lise 1993xAudibert, F.M. and Lise, L.D. Immunol. Today. 1993; 14: 281–284Abstract | Full Text PDF | PubMedSee all ReferencesAudibert and Lise 1993). Characterization of the nonclonal receptors of the innate immune system responsible for the adjuvant activity, and, evidently, for the associated side effects, would provide a powerful alternative approach, which would ultimately allow one to target these receptors directly. In one example of such a rational approach, fusion of an antigen with C3dg, a product of complement activation, resulted in dramatic potentiation of a specific immune response to the fused antigen (Dempsey et al 1996xDempsey, P.W., Allison, M.E., Akkaraju, S., Goodnow, C.C., and Fearon, D.T. Science. 1996; 271: 348–350Crossref | PubMedSee all ReferencesDempsey et al 1996).Rational approaches to vaccine design based on the detailed understanding of the molecular mechanisms of innate immunity should ultimately allow one not only to induce a specific adaptive immune response but also the desired effector mechanism without the accompanying damage to the host tissues.

MyD88 Is an Adaptor Protein in the hToll/IL-1 Receptor Family Signaling Pathways

The Toll-mediated signaling cascade using the NF-kappaB pathway has been shown to be essential for immune responses in adult Drosophila, and we recently reported that a human homolog of the Drosophila Toll protein induces various immune response genes via this pathway. We now demonstrate that signaling by the human Toll receptor employs an adaptor protein, MyD88, and induces activation of NF-kappaB via the Pelle-like kinase IRAK and the TRAF6 protein, similar to IL-1R-mediated NF-kappaB activation. However, we find that Toll and IL-1R signaling pathways are not identical with respect to AP-1 activation. Finally, our findings implicate MyD88 as a general adaptor/regulator molecule for the Toll/IL-1R family of receptors for innate immunity.

Regulation of adaptive immunity by the innate immune system

Twenty years after the proposal that pattern recognition receptors detect invasion by microbial pathogens, the field of immunology has witnessed several discoveries that have elucidated receptors and signaling pathways of microbial recognition systems and how they control the generation of T and B lymphocyte–mediated immune responses. However, there are still many fundamental questions that remain poorly understood, even though sometimes the answers are assumed to be known. Here, we discuss some of these questions, including the mechanisms by which pathogen-specific innate immune recognition activates antigen-specific adaptive immune responses and the roles of different types of innate immune recognition in host defense from infection and injury.

Toll-like receptors control activation of adaptive immune responses.

Mechanisms that control the activation of antigen-specific immune responses in vivo are poorly understood. It has been suggested that the initiation of adaptive immune responses is controlled by innate immune recognition. Mammalian Toll-like receptors play an essential role in innate immunity by recognizing conserved pathogen-associated molecular patterns and initiating the activation of NF-κB and other signaling pathways through the adapter protein, MyD88. Here we show that MyD88-deficient mice have a profound defect in the activation of antigen-specific T helper type 1 (TH1) but not TH2 immune responses. These results suggest that distinct pathways of the innate immune system control activation of the two effector arms of adaptive immunity.

Innate immunity: impact on the adaptive immune response

For many years, innate immunity has been considered as a separate entity from the adaptive immune response and has been regarded to be of secondary importance in the hierarchy of immune functions. For the past few years, however, interest in innate immunity has grown enormously, so that now it is studied intensively in many laboratories that seek to integrate these two distinct types of immune function. Our intent in this review is to point out the similarities and differences in these two types of host response to infection, and to indicate our present level of understanding of how these can be integrated into a more complete description of the immune response.