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Innate immunity: impact on the adaptive immune response
Innate immunity: impact on the adaptive immune response Ruslan Medzhitov and Charles A Janeway Jr 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.
Address Section of Immunobiology, Yale University School of Medicine and Howard Hughes Medical Institute, PO Box 208011, New Haven, CT 06520-8011, USA Correspondence: Charles A Janeway Jr Current Opinion in Immunology 1997, 9:4-9 Electronic identifier: 0952-7915-009-00004
isms, whereas adaptive immunity is found only in vertebrates. Second, innate immune recognition distinguishes self from non-self perfectly, a condition unfortunately not met by the adaptive immune response. Third, the innate immune system uses receptors that are ancient in their lineage, whereas adaptive immunity appears to use the same effector mechanisms guided by clonally specific antibodies and T C R s encoded in rearranging genes of the Ig gene superfamily [3]. In this article, we will attempt to answer four questions: firstly, what are the mechanisms of innate immune recognition, and what is their role in adaptive immunity? Secondly, what is the nature of receptors on host cells that recognize pathogens? Thirdly, how do innate components of immunity control the initiation of the adaptive immune response? And finally, how does the immune system determine which effector mechanism to induce against a given pathogen?
© Current Biology Ltd ISSN 0959-7915 Abbreviations APC antigen-presentingcell IFN interferon IL interleukin NK natural killer PAMP pathogen-associatedmolecular pattern PRR pattern-recognitionreceptor TCR T cell receptor TGF transforming growth factor TNF tumor necrosis factor
Introduction
Adaptive immunity has been intensively studied with artificial antigens, such as haptens and foreign serum proteins, leading to a precise if incomplete understanding of many of the cells, proteins, and genes involved. T h e basic paradigm of adaptive immunity, clonal selection, was proposed nearly forty years ago, and to this day it forms the background for most studies on adaptive immunity. Recefit studies of host defense against microbial pathogens, however, have demonstrated that the type of effector response generated is dependent on the innate immune response as well. Indeed, it is possible to say that recognition of foreign or non-self proteins is controlled by the rearranging genes that encode specific, clonally distributed receptors, but the functional outcome of most responses to pathogens and even the initiation of the response itself is determined by the type of innate immune response they elicit [1,2"]. T h e innate immune system is believed to have predated the adaptive immune response on several grounds. First, innate host defenses are found in all multicellular organ-
Mechanisms
of innate
immune
recognition
T h e immune system has evolved under tremendous selective pressure imposed by pathogens. As a result, all multicellular organisms have developed the ability to recognize invading microbes and to eliminate them efficiently without causing damage to self. T h e problem with recognizing pathogens is their enormous variability and molecular heterogeneity, however, which is further aggravated by the high mutational rate so characteristic of microorganisms. Also, prior to the development of somatic mechanisms of generating recognition repertoire d i v e r s i t y - - t h e hallmark of adaptive i m m u n i t y - - t h e r e was a certain upper limit on the number of recognition molecules which could be encoded in the genomes of the hosts. Therefore, relatively few germline encoded molecules have had to be able to recognize a vast variety of the molecular structures associated with pathogens. All these considerations help to specify the requirements for the possible targets of innate immune recognition: Firstly, molecular structures recognized by the immune system must be shared by large groups of pathogens, and thus must represent molecular patterns rather then particular structures. Secondly, this implies that these molecular patterns must be conserved products of microbial metabolism, which are not subject to antigenic variability: even though the immune system selects against these patterns, pathogens cannot 'change' them because they are essential for the survival or pathogenicity of the microorganisms, and any attempts to change them are lethal to the microbe, or render it nonpathogenic.
Innate immunity: impact on the adaptive immune response Medzhitovand Janeway
Finally, the overall effect of immune recognition--the destruction of the target--requires that the recognized structures be absolutely distinct from self-antigens. T h e major consequence of this requirement is the ability of the innate immune system to discriminate between self and non-self. T h e invariant molecular structures in pathogens that meet the above requirements represent the main targets of innate immune recognition, and we shall call them pathogen-associated molecular patterns (PAMPs). T h e features characteristic of PAMPs can be demonstrated by several well known examples of microbial stimulators of innate immune responses. Thus, the general structure of lipopolysaccharides and teichoic acids are shared by all gram~negative and gram-positive bacteria, respectively; the unmethylated CpG motif is characteristic of bacterial but not mammalian DNA; double-stranded RNA represents a structural signature of RNA viruses; and mannans are conserved components of yeast cell walls. None of these structures is made by the host organism and all of them are shared by large groups of pathogens and are absolutely essential for their physiology. T h e host organisms have developed a set of nonclonal receptors which can recognize PAMPs and, therefore, the presence of pathogens. These receptors have a broad specificity, because they can recognize a number of different ligands, as long as the ligands share a common molecular pattern, and therefore we call them patternrecognition receptors (PRRs). T h e main distinction of PRRs from clonally-distributed antigen receptors of T and B lymphocytes is that their specificities are germline encoded, that is, they arise over evolutionary time due to selection by pathogens at the populational level. PRRs
5
are strategically expressed on cells that are the first to encounter pathogens during infection, such as surface epithelia, and also on all types of effector cells of the innate immune system, including APCs. Recognition of pathogens (specifically, PAMPs) by PRRs results in the activation of various types of innate immune responses and often represents a direct induction of effector functions. We shall next describe the families of molecules that contribute to these recognition processes. Families of proteins with the characteristics of PRRs As opposed to the antigen receptors of adaptive immunity, which are encoded exclusively by rearranging members of the Ig superfamily, innate immune recognition is not mediated by members of a single protein family. Rather, members of several protein families have been adapted to function as PRRs. Other members of these families are used in different molecular recognition processes not necessarily related to immunity. Currently, we can distinguish seven protein families that are believed to play a central role in forming PRRs (Table 1). T h e C-type lectins, including the collectins and the receptors expressed by natural killer (NK) cells and macrophages; proteins with leucine-rich regions that mediate many protein-protein interactions, baat also encode a number of PRRs such as CD14, the cellular receptor for LPS, and a T O L L homolog which we have recently identified; the scavenger receptors; the pentraxins, components of the acute phase reaction that are synthesized in the liver and released into the plasma in response to pathogens; lipid transferases, such as the LPS binding protein; integrins; and complement control
Table I Pattern recognition molecules of the Innate Immune system. Protein family
Site of expression
Example
Ligands
Known functions
References
C-type lectins Humoral
Plasma protein
Collectins (MBL)
Opsonization, activation of complement (lectin pathway) Induces macrophage tumoricidal activity Phagocylosis Phagocylosis Cytolytio function, IFN-y secretion Inhibition of activation
[25,26]
Mecrophage C-type lectin Mecrophage mannoas receptor DEC 205 NKRop1 Ly49
Bacterial and viral carbohydrates GalNAc receptor Terminal mannose Terminal mannose Unknown CHO MHC class I (CHO?)
CD14 TOLL homolog RP105
LPS Unknown ligand Unknown
Signals cells Signals NF~B Mitogenic for B cells
[16',31] (a) [32 °]
Cellular
Macrophege, Macrophage, Macrophage, NK NK
dendritic cell dendritic cell dendritic cell cells cells
[27"] [28] [29"] [30J [30]
Leucine-rich proteins
Mecrophege, epithelial cells Monocytas, others B cells
Scavenger receptors
Mecrophage Macrophage subset T cells (cattle)
Mecrophege scavenger receptor MARCO WC1
Bacterial cell walls Bacterial cell walls Unknown
Phagocytosis Unknown Unknown
[33] [34] [35]
Pentraxins
Plasma protein Plasma protein
C-reactive protein Serum amyloid P
Phosphatidyl choline Bacterial cell walls
Opsonize, activate complement Opsonize, activate complement
[36] [37]
Lipid transfersses
Plasma protein Plasma protein
LBP BPlP
LPS, other LS LPS, other LS
Bind LPS, transfer to CD14 Becteriocldal activity
[38] [39]
Macrophage, dendritic cell, NK, T cells
CD11 b,c:CD18
LPS
Signal cells, phagocytosis
[40 °]
Integrins
(a) A mammalian homoiog of Drosophila TOLL protein (R Medzhitov, CA Janeway Jr, unpublished data); BP1P, bactericidal GalNAc, N-ecetylgalactoasmine; LBP, LPS binding protein; LPS, lipopolyseccheride; LS, liposaccharide; MBL, mannon-binding lectin.
permeability increasing protein; CHO, carbohydrate;
6
Innate immunity
proteins. Interestingly, so far no proteins of the Ig gene superfamily are known to function as PRRs, although such proteins play a critical role in costimulation and in the recognition of foreign antigens.
Induction of costimulatory molecules Adaptive immunity is mediated by T and B lymphocytes bearing clonally-distributed antigen receptors. T h e specificities of these receptors are generated by somatic mechanisms, and therefore are not products of natural selection directed by pathogens. Rather, several random processes contribute to the generation of the specificities of antigen receptors. Consequently, each lymphocyte can have a receptor with unpredicted specificity. In particular, a mature peripheral lymphocyte can have a receptor specific for a self-antigen. Therefore, a signal received through the antigen receptor is not sufficient on its own for the activation of naive lymphocytes. Indeed, it has been well documented that a second so-called costimulatory signal is required for lymphocyte stimulation [4]. Because activation of lymphocytes is only appropriate when they are specific to pathogen-derived antigens, we believe that the function of the costimulatory activity is to signal the presence of a pathogen. This requires that the expression of costimulatory activity be controlled by pathogen recognition [3,5], although other signals (e.g. those caused by trauma or surgery) may be able to induce costimulation expression as well [6]. As we discussed above, pathogen recognition is mediated by the nonclonal, innate recognition system which, it is proposed, existed prior to the development of adaptive immunity, and is based on the recognition of PAMPs by PRRs. PRRs are perfectly able to discriminate self from non-self pathogen-associated structures not produced by the host because they evolved to recognize non-self. Therefore, the signals induced by the ligation of PRRs would signal the presence of a pathogen and would be interpreted as such by the rest of the immune system. The endogenous signals induced by PAMPs can be grouped into the following three categories: Signals that mediate the inflammatory response, including IL-1, tumor necrosis factor (TNF)-a, IL-6, type I interferons (IFNs), and various chemokines. Signals that function as costimulators of T cell activation; so far only two molecules--B7.1 and B7.2--can be included in this category with certainty. Other molecules, such as intercellular adhesion molecule (ICAM)-I, that contribute to various aspects of T cell stimulation, do not share all the critical attributes of costimulatory activity, and we do not consider them to be costimulators. Signals that control the induction of effector functions; these include IL-4, IL-5, IL-10, IL-12, transforming growth factor (TGF)-I3, and IFN- T.
Inflammation is a multicomponent antigen-nonspecific stereotyped reaction to infection which has several generalized effects on the adaptive immune response. All inflammatory cytokines can be induced by different types of pathogens and can stimulate multiple effector functions of innate immunity. Additionally, these cytokines potentiate adaptive responses at the effector stages. Type I IFNs (~ and ~) are induced by viruses and, among other effects, strongly Upregulate the expression of the MHC class I molecules, thus increasing the efficiency of presentation of viral peptides to the cytotoxic T cells [7]. IL-1, T N F - a , and chemokines direct the migration of antigen-specific lymphocytes, along with other effector cells, to the site of infection either by inducing the expression of adhesion molecules on endothelial cells (IL-1 and T N F - ~ ) [8], or by stimulating chemotaxis (chemokines) [9]. Finally, IL-6 induces the terminal differentiation of B lymphocytes into Ig-producing plasma cells [10]. These examples demonstrate the acquisition of new functions by cytokines with the development of adaptive immunity. Initially, it is suggested, responses induced by PRRs upon recognition of pathogens consisted of host defense mechanisms that are found in all organisms, such as phagocytosis, the production of antibacterial peptides, and other microbicidal and antiviral mechanisms [1]. When vertebrates evolved as a separate sub-phylum, these responses retained their original function, but over time acquired new functions as well. One of these functions was to induce the expression of costimulatory molecules on the cell surface of APCs, another was to facilitate pathogen uptake and degradation. T h e latter function was then further adapted to present unique signals from pathogens in the form of MHC-bound peptides to the receptors on T cells. Thus, the presence of the pathogen is recognized by the APC by the binding of one of its PRR to PAMPs, and the specific pathogen-derived antigens are presented by the same APC through the processing and presentation of peptides specific to that pathogen. This whole mechanism ensures that a T cell will normally receive both signals necessary for activation only if the peptide recognized by the T C R is derived from the pathogen that initially induced the costimulatory activity [11]. A number of pathogen products have been shown to be able to induce the expression of costimulatory molecules such as B7.1 and B7.2: bacterial DNA [12°], viral RNA [13], mycobacterial membranes [14], Neisset~a porin [15], LPS, mannans, glycans, etc. [16°,17,18]. Each of these substances induces costimulatory molecules on all cells of a given type, and this ability is thought to account for the potency of many adjuvants. Because self-antigens lack PAMPs, they cannot induce costimulatory activity, and therefore T cells specific for self-antigens normally cannot be activated. This way, the nonclonal innate immune system controls self/non-self discrimination in the adaptive immune response by regulating the expression of costimulatory molecules. This means also that the innate
Innate immunity: impact on the adaptive immune response Medzhitov and Janeway
members of the Ig superfamily, notably B7.1 and B7.2 (B7 molecules). T h e T cell, in turn, bears two members of the Ig superfamily that recognize and respond to these signals. First, the T C R itself is a highly variable member of the Ig superfamily. Recognition of specific peptide-MHC complexes mediates clonal responses to pathogens under the control of signals received through a second receptor that is also a member of the Ig gene superfamily, CD28, which binds to B7 molecules. In the absence of a signal through CD28, no response occurs and the T cell becomes tolerant or anergic. In the presence of signals through CD28, the T cell is activated, and this subsequently leads to the expression of surface molecules, TNF-ct and -13, Fas ligand (L), CD40L, CD30L, and CD27L on the T cells, as well as the secretion of cytokines. In turn, these act in an antigen-specific fashion on target cells that display the appropriate antigen and that bear receptors
immune system actually controls the activation of all adaptive immune responses [3,5], although in some cases, such as graft rejection which is induced by APCs bearing non-self MHC molecules and co-stimulatory capacity, this control may not be obvious [6]. Cognate
interactions
in a d a p t i v e
7
immunity
T h e cognate interactions involve the specific recognition of antigen on the surfat:e of another cell, and are a feature of adaptive immunity. T h e y are triggered by PAMPs acting on PRRs of APCs. This action has two effects, as noted earlier, the induction of expression of costimulatory molecules on the APC surface, and the production of pathogen-specific signals in the form of MHC-peptide complexes. This combination is ideal for stimulating a T cell response to the pathogen [4]. T h e costimulators that are induced by the binding of PAMPs to PRRs are Figure 1 Recognition of a pathogenby PRRs induces a set of endogenous signals, includingcostimulatory molecules (BT),
~..1- Pathogen
inflammatoryand effectorcytokines, and CDld molecules.Additionally, some cells can phagocytose the
pathogen (not shown), process its protein constituents, and present its peptides to T cells. Recognition of peptides derivedfroma pathogen, along with costimulatory molecules induced by the pathogen, results in T cell activation. Effectorcytokinesinducedby the pathogen instructthe activatedT cells to differentiateinto a particulareffector
cell type (T1 or T2). ActivatedT cells then deliveran induciblesignal(usually a memberof the TNF family,such as CD40L or FasL)to the target cell in an antigen-specific manner:the target cells of T1 and T2 being macrophages and B cells, respectively.L, ligand.
CD40L, FasL,CD30L,CD27L
/ © 1997 Current Opinion in Immunology
,~~Macrophage ~
8
Innate immunity
for the T N F family members as well as for cytokines. Cytokines are secreted in a polarized fashion when the T cell encounters its specific ligand on a target cell surface. If the target cell is a somatic cell, such as a liver cell, CD8 + T cells will kill it by means of any of the pathways of apoptosis: the T N F pathway, the FasL pathway, and/or the analogous perforin/granzyme pathway. If the target cell is an APe, such as B cells, macrophages, or dendritic cells, CD40L can activate it to express higher levels of B7 molecules [19], providing feedback stimulation of the immune response, and activating the B cells to secrete antibody or the macrophages to kill their ingested bacteria (Fig. 1).
Innate immune system control of effector cytokines Host organisms can be infected by very different types of pathogens which require quite different means of elimination. Therefore, a number of distinct effector mechanisms have evolved to be used against different types of pathogens. Cells and molecules of the innate immune system are specialized to perform a particular effector function. Because PRRs are strategically expressed on the effector cells of the innate immune system, and because they can directly activate effector functions, recognition of a pathogen by the nonclonal system induces the appropriate effector response. That is, the innate immune system can not only discriminate self from non-self, but can also discriminate between different types of pathogens so that an effective response will be mounted. Lymphocytes of the adaptive immune system, on the other hand, are all made 'equal', in that they are not specialized to any particular type of response prior to activation. Each lymphocyte is endowed with the random specificity of its antigen receptor, which may turn out to be specific for antigens derived from any kind of pathogen, each of which may require quite different types of effector responses. Naive lymphocytes are pluripotent, therefore, in that they can differentiate along different pathways to become distinct effector cells, depending on the additional signals received during activation. These signals are induced by pathogens in the effector cells of the innate immune system [20]. Different effector cells express different sets of cytokines upon stimulation of PRRs expressed on these cells. Major effector cytokines and their cell sources are shown in Table 2. All the cytokines shown in Table in an infection and determine the adaptive immune response. Type IFN-y) induce the differentiation
2 are induced early effector type of the 1 cytokines (IL-12, of T cells into T h l
Table 2 Major effector cytokines and their cell sources.
Cell type Macrophages Macrophages Natural killer cells Mast cells, basophils Eosinophils Epithelial cells, macrophages NK T cells
Effector cytokine
Effector response
IL-12 IL-10 IFN-7 IL-4 IL-5 TGF-I~ IL-4
Th 1 Th2 Thl, IgG 2 Th2, IgG1, IgE IgE IgA Th2, IgG1, IgE
effector cells, whereas type 2 cytokines (IL-4, IL-10) induce the Th2 differentiation pathway [21]. T h e same effects are seen in the CD8 + T cell differentiation pathway [22]. Similarly, effector cytokines control the isotype switch of the antibodies produced by B cells [23]. One notable exception of the cell types producing effector cytokines is NK T cells. These cells are not directly induced to express IL-4 by pathogens, but rather require the recognition of C D l d (in the mouse CDI.1 and CD1.2) molecules [24"']. C D l d itself is induced by bacterial products on epithelial cells, mononuclear phagocytes and B cells, however (R Medzhitov, CA Janeway Jr, unpublished data). It is likely that other nonclassical M H C molecules induced by pathogens on epithelial cells and APCs can serve as ligands for unconventional T cell subpopulations that share characteristics of the innate immune response.
Conclusions T h e functioning of the immune system is based on two distinct recognition systems: innate and adaptive. T h e induction of an appropriate effector function in clonal cells is mediated by the innate immune system, while both the adaptive and innate immune responses control self/non-self discrimination. T h e innate, nonclonal system controls the initiation of the adaptive immune response by regulating the expression of costimulatory activity on APCs, and instructs the adaptive immune system to develop a particular effector response by releasing effector cytokines. T h e functioning of iymphocytes bearing clonally-rearranged receptors is absolutely dependent on these signals that are provided by the innate recognition system. Thus, we consider the innate and adaptive immune responses to be integrated in the vertebrate host as a single immune system, with the innate response preceding, and being necessary for, the adaptive i m m u n e response.
Acknowledgements Supported in part by National Institutes of Health grant AI-26810 and the Howard Hughes Medical Institute.
Innate immunity: impact on the adaptive immune response Medzhitov and Jan•way
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Address Section of Immunobiology, Yale University School of Medicine and Howard Hughes Medical Institute, PO Box 208011, New Haven, CT 06520-8011, USA Correspondence: Charles A Janeway Jr Current Opinion in Immunology 1997, 9:4-9 Electronic identifier: 0952-7915-009-00004
isms, whereas adaptive immunity is found only in vertebrates. Second, innate immune recognition distinguishes self from non-self perfectly, a condition unfortunately not met by the adaptive immune response. Third, the innate immune system uses receptors that are ancient in their lineage, whereas adaptive immunity appears to use the same effector mechanisms guided by clonally specific antibodies and T C R s encoded in rearranging genes of the Ig gene superfamily [3]. In this article, we will attempt to answer four questions: firstly, what are the mechanisms of innate immune recognition, and what is their role in adaptive immunity? Secondly, what is the nature of receptors on host cells that recognize pathogens? Thirdly, how do innate components of immunity control the initiation of the adaptive immune response? And finally, how does the immune system determine which effector mechanism to induce against a given pathogen?
© Current Biology Ltd ISSN 0959-7915 Abbreviations APC antigen-presentingcell IFN interferon IL interleukin NK natural killer PAMP pathogen-associatedmolecular pattern PRR pattern-recognitionreceptor TCR T cell receptor TGF transforming growth factor TNF tumor necrosis factor
Introduction
Adaptive immunity has been intensively studied with artificial antigens, such as haptens and foreign serum proteins, leading to a precise if incomplete understanding of many of the cells, proteins, and genes involved. T h e basic paradigm of adaptive immunity, clonal selection, was proposed nearly forty years ago, and to this day it forms the background for most studies on adaptive immunity. Recefit studies of host defense against microbial pathogens, however, have demonstrated that the type of effector response generated is dependent on the innate immune response as well. Indeed, it is possible to say that recognition of foreign or non-self proteins is controlled by the rearranging genes that encode specific, clonally distributed receptors, but the functional outcome of most responses to pathogens and even the initiation of the response itself is determined by the type of innate immune response they elicit [1,2"]. T h e innate immune system is believed to have predated the adaptive immune response on several grounds. First, innate host defenses are found in all multicellular organ-
Mechanisms
of innate
immune
recognition
T h e immune system has evolved under tremendous selective pressure imposed by pathogens. As a result, all multicellular organisms have developed the ability to recognize invading microbes and to eliminate them efficiently without causing damage to self. T h e problem with recognizing pathogens is their enormous variability and molecular heterogeneity, however, which is further aggravated by the high mutational rate so characteristic of microorganisms. Also, prior to the development of somatic mechanisms of generating recognition repertoire d i v e r s i t y - - t h e hallmark of adaptive i m m u n i t y - - t h e r e was a certain upper limit on the number of recognition molecules which could be encoded in the genomes of the hosts. Therefore, relatively few germline encoded molecules have had to be able to recognize a vast variety of the molecular structures associated with pathogens. All these considerations help to specify the requirements for the possible targets of innate immune recognition: Firstly, molecular structures recognized by the immune system must be shared by large groups of pathogens, and thus must represent molecular patterns rather then particular structures. Secondly, this implies that these molecular patterns must be conserved products of microbial metabolism, which are not subject to antigenic variability: even though the immune system selects against these patterns, pathogens cannot 'change' them because they are essential for the survival or pathogenicity of the microorganisms, and any attempts to change them are lethal to the microbe, or render it nonpathogenic.
Innate immunity: impact on the adaptive immune response Medzhitovand Janeway
Finally, the overall effect of immune recognition--the destruction of the target--requires that the recognized structures be absolutely distinct from self-antigens. T h e major consequence of this requirement is the ability of the innate immune system to discriminate between self and non-self. T h e invariant molecular structures in pathogens that meet the above requirements represent the main targets of innate immune recognition, and we shall call them pathogen-associated molecular patterns (PAMPs). T h e features characteristic of PAMPs can be demonstrated by several well known examples of microbial stimulators of innate immune responses. Thus, the general structure of lipopolysaccharides and teichoic acids are shared by all gram~negative and gram-positive bacteria, respectively; the unmethylated CpG motif is characteristic of bacterial but not mammalian DNA; double-stranded RNA represents a structural signature of RNA viruses; and mannans are conserved components of yeast cell walls. None of these structures is made by the host organism and all of them are shared by large groups of pathogens and are absolutely essential for their physiology. T h e host organisms have developed a set of nonclonal receptors which can recognize PAMPs and, therefore, the presence of pathogens. These receptors have a broad specificity, because they can recognize a number of different ligands, as long as the ligands share a common molecular pattern, and therefore we call them patternrecognition receptors (PRRs). T h e main distinction of PRRs from clonally-distributed antigen receptors of T and B lymphocytes is that their specificities are germline encoded, that is, they arise over evolutionary time due to selection by pathogens at the populational level. PRRs
5
are strategically expressed on cells that are the first to encounter pathogens during infection, such as surface epithelia, and also on all types of effector cells of the innate immune system, including APCs. Recognition of pathogens (specifically, PAMPs) by PRRs results in the activation of various types of innate immune responses and often represents a direct induction of effector functions. We shall next describe the families of molecules that contribute to these recognition processes. Families of proteins with the characteristics of PRRs As opposed to the antigen receptors of adaptive immunity, which are encoded exclusively by rearranging members of the Ig superfamily, innate immune recognition is not mediated by members of a single protein family. Rather, members of several protein families have been adapted to function as PRRs. Other members of these families are used in different molecular recognition processes not necessarily related to immunity. Currently, we can distinguish seven protein families that are believed to play a central role in forming PRRs (Table 1). T h e C-type lectins, including the collectins and the receptors expressed by natural killer (NK) cells and macrophages; proteins with leucine-rich regions that mediate many protein-protein interactions, baat also encode a number of PRRs such as CD14, the cellular receptor for LPS, and a T O L L homolog which we have recently identified; the scavenger receptors; the pentraxins, components of the acute phase reaction that are synthesized in the liver and released into the plasma in response to pathogens; lipid transferases, such as the LPS binding protein; integrins; and complement control
Table I Pattern recognition molecules of the Innate Immune system. Protein family
Site of expression
Example
Ligands
Known functions
References
C-type lectins Humoral
Plasma protein
Collectins (MBL)
Opsonization, activation of complement (lectin pathway) Induces macrophage tumoricidal activity Phagocylosis Phagocylosis Cytolytio function, IFN-y secretion Inhibition of activation
[25,26]
Mecrophage C-type lectin Mecrophage mannoas receptor DEC 205 NKRop1 Ly49
Bacterial and viral carbohydrates GalNAc receptor Terminal mannose Terminal mannose Unknown CHO MHC class I (CHO?)
CD14 TOLL homolog RP105
LPS Unknown ligand Unknown
Signals cells Signals NF~B Mitogenic for B cells
[16',31] (a) [32 °]
Cellular
Macrophege, Macrophage, Macrophage, NK NK
dendritic cell dendritic cell dendritic cell cells cells
[27"] [28] [29"] [30J [30]
Leucine-rich proteins
Mecrophege, epithelial cells Monocytas, others B cells
Scavenger receptors
Mecrophage Macrophage subset T cells (cattle)
Mecrophege scavenger receptor MARCO WC1
Bacterial cell walls Bacterial cell walls Unknown
Phagocytosis Unknown Unknown
[33] [34] [35]
Pentraxins
Plasma protein Plasma protein
C-reactive protein Serum amyloid P
Phosphatidyl choline Bacterial cell walls
Opsonize, activate complement Opsonize, activate complement
[36] [37]
Lipid transfersses
Plasma protein Plasma protein
LBP BPlP
LPS, other LS LPS, other LS
Bind LPS, transfer to CD14 Becteriocldal activity
[38] [39]
Macrophage, dendritic cell, NK, T cells
CD11 b,c:CD18
LPS
Signal cells, phagocytosis
[40 °]
Integrins
(a) A mammalian homoiog of Drosophila TOLL protein (R Medzhitov, CA Janeway Jr, unpublished data); BP1P, bactericidal GalNAc, N-ecetylgalactoasmine; LBP, LPS binding protein; LPS, lipopolyseccheride; LS, liposaccharide; MBL, mannon-binding lectin.
permeability increasing protein; CHO, carbohydrate;
6
Innate immunity
proteins. Interestingly, so far no proteins of the Ig gene superfamily are known to function as PRRs, although such proteins play a critical role in costimulation and in the recognition of foreign antigens.
Induction of costimulatory molecules Adaptive immunity is mediated by T and B lymphocytes bearing clonally-distributed antigen receptors. T h e specificities of these receptors are generated by somatic mechanisms, and therefore are not products of natural selection directed by pathogens. Rather, several random processes contribute to the generation of the specificities of antigen receptors. Consequently, each lymphocyte can have a receptor with unpredicted specificity. In particular, a mature peripheral lymphocyte can have a receptor specific for a self-antigen. Therefore, a signal received through the antigen receptor is not sufficient on its own for the activation of naive lymphocytes. Indeed, it has been well documented that a second so-called costimulatory signal is required for lymphocyte stimulation [4]. Because activation of lymphocytes is only appropriate when they are specific to pathogen-derived antigens, we believe that the function of the costimulatory activity is to signal the presence of a pathogen. This requires that the expression of costimulatory activity be controlled by pathogen recognition [3,5], although other signals (e.g. those caused by trauma or surgery) may be able to induce costimulation expression as well [6]. As we discussed above, pathogen recognition is mediated by the nonclonal, innate recognition system which, it is proposed, existed prior to the development of adaptive immunity, and is based on the recognition of PAMPs by PRRs. PRRs are perfectly able to discriminate self from non-self pathogen-associated structures not produced by the host because they evolved to recognize non-self. Therefore, the signals induced by the ligation of PRRs would signal the presence of a pathogen and would be interpreted as such by the rest of the immune system. The endogenous signals induced by PAMPs can be grouped into the following three categories: Signals that mediate the inflammatory response, including IL-1, tumor necrosis factor (TNF)-a, IL-6, type I interferons (IFNs), and various chemokines. Signals that function as costimulators of T cell activation; so far only two molecules--B7.1 and B7.2--can be included in this category with certainty. Other molecules, such as intercellular adhesion molecule (ICAM)-I, that contribute to various aspects of T cell stimulation, do not share all the critical attributes of costimulatory activity, and we do not consider them to be costimulators. Signals that control the induction of effector functions; these include IL-4, IL-5, IL-10, IL-12, transforming growth factor (TGF)-I3, and IFN- T.
Inflammation is a multicomponent antigen-nonspecific stereotyped reaction to infection which has several generalized effects on the adaptive immune response. All inflammatory cytokines can be induced by different types of pathogens and can stimulate multiple effector functions of innate immunity. Additionally, these cytokines potentiate adaptive responses at the effector stages. Type I IFNs (~ and ~) are induced by viruses and, among other effects, strongly Upregulate the expression of the MHC class I molecules, thus increasing the efficiency of presentation of viral peptides to the cytotoxic T cells [7]. IL-1, T N F - a , and chemokines direct the migration of antigen-specific lymphocytes, along with other effector cells, to the site of infection either by inducing the expression of adhesion molecules on endothelial cells (IL-1 and T N F - ~ ) [8], or by stimulating chemotaxis (chemokines) [9]. Finally, IL-6 induces the terminal differentiation of B lymphocytes into Ig-producing plasma cells [10]. These examples demonstrate the acquisition of new functions by cytokines with the development of adaptive immunity. Initially, it is suggested, responses induced by PRRs upon recognition of pathogens consisted of host defense mechanisms that are found in all organisms, such as phagocytosis, the production of antibacterial peptides, and other microbicidal and antiviral mechanisms [1]. When vertebrates evolved as a separate sub-phylum, these responses retained their original function, but over time acquired new functions as well. One of these functions was to induce the expression of costimulatory molecules on the cell surface of APCs, another was to facilitate pathogen uptake and degradation. T h e latter function was then further adapted to present unique signals from pathogens in the form of MHC-bound peptides to the receptors on T cells. Thus, the presence of the pathogen is recognized by the APC by the binding of one of its PRR to PAMPs, and the specific pathogen-derived antigens are presented by the same APC through the processing and presentation of peptides specific to that pathogen. This whole mechanism ensures that a T cell will normally receive both signals necessary for activation only if the peptide recognized by the T C R is derived from the pathogen that initially induced the costimulatory activity [11]. A number of pathogen products have been shown to be able to induce the expression of costimulatory molecules such as B7.1 and B7.2: bacterial DNA [12°], viral RNA [13], mycobacterial membranes [14], Neisset~a porin [15], LPS, mannans, glycans, etc. [16°,17,18]. Each of these substances induces costimulatory molecules on all cells of a given type, and this ability is thought to account for the potency of many adjuvants. Because self-antigens lack PAMPs, they cannot induce costimulatory activity, and therefore T cells specific for self-antigens normally cannot be activated. This way, the nonclonal innate immune system controls self/non-self discrimination in the adaptive immune response by regulating the expression of costimulatory molecules. This means also that the innate
Innate immunity: impact on the adaptive immune response Medzhitov and Janeway
members of the Ig superfamily, notably B7.1 and B7.2 (B7 molecules). T h e T cell, in turn, bears two members of the Ig superfamily that recognize and respond to these signals. First, the T C R itself is a highly variable member of the Ig superfamily. Recognition of specific peptide-MHC complexes mediates clonal responses to pathogens under the control of signals received through a second receptor that is also a member of the Ig gene superfamily, CD28, which binds to B7 molecules. In the absence of a signal through CD28, no response occurs and the T cell becomes tolerant or anergic. In the presence of signals through CD28, the T cell is activated, and this subsequently leads to the expression of surface molecules, TNF-ct and -13, Fas ligand (L), CD40L, CD30L, and CD27L on the T cells, as well as the secretion of cytokines. In turn, these act in an antigen-specific fashion on target cells that display the appropriate antigen and that bear receptors
immune system actually controls the activation of all adaptive immune responses [3,5], although in some cases, such as graft rejection which is induced by APCs bearing non-self MHC molecules and co-stimulatory capacity, this control may not be obvious [6]. Cognate
interactions
in a d a p t i v e
7
immunity
T h e cognate interactions involve the specific recognition of antigen on the surfat:e of another cell, and are a feature of adaptive immunity. T h e y are triggered by PAMPs acting on PRRs of APCs. This action has two effects, as noted earlier, the induction of expression of costimulatory molecules on the APC surface, and the production of pathogen-specific signals in the form of MHC-peptide complexes. This combination is ideal for stimulating a T cell response to the pathogen [4]. T h e costimulators that are induced by the binding of PAMPs to PRRs are Figure 1 Recognition of a pathogenby PRRs induces a set of endogenous signals, includingcostimulatory molecules (BT),
~..1- Pathogen
inflammatoryand effectorcytokines, and CDld molecules.Additionally, some cells can phagocytose the
pathogen (not shown), process its protein constituents, and present its peptides to T cells. Recognition of peptides derivedfroma pathogen, along with costimulatory molecules induced by the pathogen, results in T cell activation. Effectorcytokinesinducedby the pathogen instructthe activatedT cells to differentiateinto a particulareffector
cell type (T1 or T2). ActivatedT cells then deliveran induciblesignal(usually a memberof the TNF family,such as CD40L or FasL)to the target cell in an antigen-specific manner:the target cells of T1 and T2 being macrophages and B cells, respectively.L, ligand.
CD40L, FasL,CD30L,CD27L
/ © 1997 Current Opinion in Immunology
,~~Macrophage ~
8
Innate immunity
for the T N F family members as well as for cytokines. Cytokines are secreted in a polarized fashion when the T cell encounters its specific ligand on a target cell surface. If the target cell is a somatic cell, such as a liver cell, CD8 + T cells will kill it by means of any of the pathways of apoptosis: the T N F pathway, the FasL pathway, and/or the analogous perforin/granzyme pathway. If the target cell is an APe, such as B cells, macrophages, or dendritic cells, CD40L can activate it to express higher levels of B7 molecules [19], providing feedback stimulation of the immune response, and activating the B cells to secrete antibody or the macrophages to kill their ingested bacteria (Fig. 1).
Innate immune system control of effector cytokines Host organisms can be infected by very different types of pathogens which require quite different means of elimination. Therefore, a number of distinct effector mechanisms have evolved to be used against different types of pathogens. Cells and molecules of the innate immune system are specialized to perform a particular effector function. Because PRRs are strategically expressed on the effector cells of the innate immune system, and because they can directly activate effector functions, recognition of a pathogen by the nonclonal system induces the appropriate effector response. That is, the innate immune system can not only discriminate self from non-self, but can also discriminate between different types of pathogens so that an effective response will be mounted. Lymphocytes of the adaptive immune system, on the other hand, are all made 'equal', in that they are not specialized to any particular type of response prior to activation. Each lymphocyte is endowed with the random specificity of its antigen receptor, which may turn out to be specific for antigens derived from any kind of pathogen, each of which may require quite different types of effector responses. Naive lymphocytes are pluripotent, therefore, in that they can differentiate along different pathways to become distinct effector cells, depending on the additional signals received during activation. These signals are induced by pathogens in the effector cells of the innate immune system [20]. Different effector cells express different sets of cytokines upon stimulation of PRRs expressed on these cells. Major effector cytokines and their cell sources are shown in Table 2. All the cytokines shown in Table in an infection and determine the adaptive immune response. Type IFN-y) induce the differentiation
2 are induced early effector type of the 1 cytokines (IL-12, of T cells into T h l
Table 2 Major effector cytokines and their cell sources.
Cell type Macrophages Macrophages Natural killer cells Mast cells, basophils Eosinophils Epithelial cells, macrophages NK T cells
Effector cytokine
Effector response
IL-12 IL-10 IFN-7 IL-4 IL-5 TGF-I~ IL-4
Th 1 Th2 Thl, IgG 2 Th2, IgG1, IgE IgE IgA Th2, IgG1, IgE
effector cells, whereas type 2 cytokines (IL-4, IL-10) induce the Th2 differentiation pathway [21]. T h e same effects are seen in the CD8 + T cell differentiation pathway [22]. Similarly, effector cytokines control the isotype switch of the antibodies produced by B cells [23]. One notable exception of the cell types producing effector cytokines is NK T cells. These cells are not directly induced to express IL-4 by pathogens, but rather require the recognition of C D l d (in the mouse CDI.1 and CD1.2) molecules [24"']. C D l d itself is induced by bacterial products on epithelial cells, mononuclear phagocytes and B cells, however (R Medzhitov, CA Janeway Jr, unpublished data). It is likely that other nonclassical M H C molecules induced by pathogens on epithelial cells and APCs can serve as ligands for unconventional T cell subpopulations that share characteristics of the innate immune response.
Conclusions T h e functioning of the immune system is based on two distinct recognition systems: innate and adaptive. T h e induction of an appropriate effector function in clonal cells is mediated by the innate immune system, while both the adaptive and innate immune responses control self/non-self discrimination. T h e innate, nonclonal system controls the initiation of the adaptive immune response by regulating the expression of costimulatory activity on APCs, and instructs the adaptive immune system to develop a particular effector response by releasing effector cytokines. T h e functioning of iymphocytes bearing clonally-rearranged receptors is absolutely dependent on these signals that are provided by the innate recognition system. Thus, we consider the innate and adaptive immune responses to be integrated in the vertebrate host as a single immune system, with the innate response preceding, and being necessary for, the adaptive i m m u n e response.
Acknowledgements Supported in part by National Institutes of Health grant AI-26810 and the Howard Hughes Medical Institute.
Innate immunity: impact on the adaptive immune response Medzhitov and Jan•way
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