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Antigen presentation
The Immune-NeuroendocrineCircuitry
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Edited by I. Berczi and A. Szentivanyi 9 2003 Elsevier Science B.V. All rights reserved
Antigen Presentation
ISTVAN BERCZI and ANDOR SZENTIVANYI
Department of Immunology, Faculty of Medicine, The University of Manitoba, Winnipeg, Manitoba R3E OW3, Canada; and Department of Internal Medicine, Faculty of Medicine, The University of South Florida, Tampa, Florida 33612, USA ABSTRACT Antigen presentation takes place by cell-to-cell interaction whereby a complex signaling process via cell surface adhesion molecules initiates the adaptive (antigen specific) immune responses. Without exception the macromolecular antigen undergoes proteolytic breakdown and peptide fractions (-~9-24 residues) are presented by antigen presenting cells (APC) in association with surface MHC antigens. External antigens are engulfed by phagocytic mononuclear cells and are digested in endosomes and the peptide fragments are joining with MHC-II molecules in endocytic vesicles (endocytic pathway of processing) prior to expression on the cell surface. The APC of this pathway are resposible for the induction of the antibody response and delayed type hypersensitivity reactions. Endogenous antigens are processed in the cytoplasm, in enzyme-containing proteosomes (cytosolic pathway) and the peptides generated are associated with MHC-I in the endoplsmic reticulum, which in turn is expressed on the surface of all nucleated cells in the body. Cytotoxic T lymphocytes recognize MHC-I-peptide complexes on the cell surface and destroy infected and cancer cells. This antigen presenting system requires the digestion of the antigen after phagocytosis, which protects against extracellular and intracellular pathogens, it exposes hidden antigenic determinents, decreases the impact of mutations by employing short peptides and allows for self-non-self discrimination. Non-classical MHC antigens are also involved in antigen presentation and specialized surface molecules (CD1) mediate carbohydrate and lipid presentation. Heat shock proteins normally serve to eliminate dead cells from tissues but also form complexes with antigen which are taken up by APC through a specific receptor (CD91). Such complexes are taken up by macrophages and dendritic cells, digested and are presented by MHC-I. The dominant role of antigen presentation in the adaptive immune system illustrates the fundamental regulatory function of adherence signals in multi-cellular organisms.
1.
INTRODUCTION
Adaptive immune reactions are mediated by lymphocyte clones that have specific receptors for the determinants (epitopes) of the antigen. Initially, the antigen was assumed to be the sole signal that instructed immunocytes to make antibodies by some sort of recognizing and copying mechanism [ 1]. Later it was realized that antibody specificity is genetically coded and that the antigen has to be digested and presented by specialized antigen presenting cells (APC) to T lyre-
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phocytes. Phagocytic mononuclear cells (monocyte-macrophages), B lymphocytes and some specialized cells (e.g., dendritic cells, Langerhans cells, Kuppfer cells) are "professional" APC that present antigen via major histocompatibility (MHC)-I and MHC-II. In the central nervous system the macrophage-related microglia and to a lesser extent, astrocytes, are involved in antigen presentation as well as in inflammatory responses. However, all nucleated cells are capable of antigen presentation by MHC-I, which is constitutively expressed by such cells. In addition, IFNy is capable of inducing the expression of MHC-II in somatic cells, which enables them to present antigens by this pathway. Major histocompatibility antigens bind peptides during their intracellular biosynthesis and carry them to the surface of APC. In turn the digested (processed) antigenic peptide-MHC complexes are recognized by T cells as "altered self" [2,3,4,5,6]. The conventional view is that the T cell receptor recognizes the MHC antigen as "self" and the peptide as "non-self' in this process. This self-nonself recognition has evolved to provide protection against autoimmune reactions while foreign invaders are attacked. The requirement for T cells to recognize antigens in the context of MHC assures that infected and cancerous cells are specifically eliminated by killer cells. However, soluble antigen, which is not processed and not associated with MHC antigens, is not capable of triggering killer T lymphocytes. This mechanism prevents the exhaustion of T cells by viremia or by other antigen that is present in the circulation [2]. 2.
THE SIGNIFICANCE OF PROCESSING
The requirement for processing has several advantages: (i) It involves the phagocytosis and digestion of the antigen, which leads to inactivation of microbes, viruses and other pathogens; (ii) Digestion and presentation allow for the presentation of epitopes from the antigens of intracellular pathogens to T cells. This leads to the selective elimination of infected or cancerous cells. (iii) Epitopes that are hidden in the native molecule, viruses etc. may be recognized after processing and presentation; (iv) It reduces the chance of avoiding recognition by mutation of the antigen; (v) It allows for self-nonself discrimination [2].
3.
ANTIGEN RECOGNITION BY T CELLS
The current consensus is that T lymphocytes recognize self-MHC antigens via their receptors (TCR). During the development of T cells, those clones that are triggered for an immune response by self-MHC are killed (selected out) in the thymus and also in the periphery. The cells that remain "recognize", but are not activated by self-MHC. The various clones will, however, be activated if the MHC molecule contains a peptide fragment for which the T cell clone shows specificity. The TCR of these cells recognizes the peptide antigen in the "context" of self-MHC as "altered self". This phenomenon is known as the MHC-restriction of T-cell activation. If the MHC component is missing, the T cell will not be activated. MHC-II presents antigens to CD4+ and MHC-I to CD8+ T cells. CD4 and CD8 are accessory recognition molecules on the surface of these T cells, which contribute to MHC recognition by the T lymphocyte. These rules apply to a[3TCR [71. MHC-II is involved in the presentation of foreign antigen-derived peptides. This is called the endocytic pathway as the antigens are ingested by endocytosis, digested and the resulting peptides presented by APC to T cells. MHC-I presents peptides by the cytosolic pathway, which are derived from the cytosol of the cell itself. While the endocytic pathway is present
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only in specialized APC, the cytosolic pathway is present in all cells of the body, as MHC-I is expressed by all somatic cells. This latter pathway serves the purpose of immunological surveillance against intracellular pathogens (e.g., viruses, some bacteria, protozoa and fungi) and cancer. CD8+ cytotoxic T lymphocytes patrol the entire body by penetrating the tissues via the high endothelial cells in capillaries and detect and kill abnormal cells expressing altered MHC-I antigens [2,3,4].
4.
PEPTIDE BINDING BY MHC
In the MHC-I molecule the ~1 and ~2 domains combine to form a single peptide binding site supported by a l]-pleated sheet floor containing eight strands bound by two ~ helices, one from ~1 and the other from ~2. I]2-microglobulin makes contact with the immunoglobulin-like ~3 domain and also with the ~ sheet floor of the ~1~2 peptide-binding region. These structures show a series of pockets studding the peptide-binding groove. Occasionally the pockets extend deep between the floor and helical walls of the binding domain [8,9,10,11]. These pockets have now been designated from A to F. MHC polymorphism is primarily related to the diversification of their peptide-binding specificities. Different alleles are meant to bind distinct sets of peptides. Hydrogen bonds, hydrophobic interactions, and generic sequence independent interactions play major roles in peptide binding. MHC molecule polymorphism directly influences recognition by TCR. Distinct alleles of MHC molecules bind and present distinct peptides to T lymphocytes [9,10,12,13]. The interaction of peptides with MHC-I is very stable and the peptides bound are of fixed length of mostly 9 (8-10) amino acids. Predominant amino acids are found in comparable positions, which are called motif or anchor amino acids, that promote binding to a particular allele of MHC-I. Most peptides presented by MHC-I are derived from cytoplasmic or nuclear proteins. Physiologically stable class I molecules are actually trimers of the MHC heavy chain, ~2-microglobulin and the peptide. These components synergize in forming a long-lived, properly-folded complex [ 15,16,17]. MHC-II bound peptides are longer and more heterogeneous in size, ranging from 12 to more than 24 residues. Anchor residues play a role in binding. These peptides are derived from proteins that have access to the endocytic pathway of antigen processing. Intracellular proteins access the class II pathway inefficiently compared with the class-I pathway, although exceptions have been reported. For class-II molecules the peptide is not needed for the maintenance of chain association at physiologic temperature and pH. MHC-II molecules bind peptides mostly via main chain atoms and not by the ends of the peptide [ 18,19,20,21 ].
5.
SYNTHESIS OF MHC-I AND MHC-II
Class-I MHC and ~2-microglobulin (~2M) are type I proteins and enter the endoplasmic reticulum (ER) via the signal recognition and transport apparatus. The MHC chain associates rapidly with an ER resident protein now termed calnexin [22]. This protein is Ca 2+sensitive and is associated with the signal sequence dependent translocation apparatus and interacts with various membrane and secreted proteins in ER. Calnexin's binding to the MHC-I chain involves both carbohydrate and protein structure recognition [23,24]. In the case of human MHC-I, this chaperone dissociates from the molecule upon binding [~2M and another chaperone, calreticulin, will
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combine with the complex [25]. At this stage the MHC-132M complex also associates with an MHC-encoded molecule called tapasin [26]. Once the MHC-~32M complex is associated with the antigenic peptide, calreticulin and tapasin dissociate from the complex, which exits the ER and moves through the Golgi network on to the cell surface by the default secretory pathway. MHC class II a and 13 chains associate soon after synthesis in the presence of the invariant chain (Ii), which is a nonpolymorphic type II membrane glycoprotein [27,28]. Ii is a family of proteins. Ii forms noncovalently associated trimes in ER, and Class II a~ dimers are quickly associate with such trimers [29,30]. Non-class II associated Ii binds to calnexin, which dissociates upon the formation of class II-Ii oligomers [31,32]. The c~[3Ii complex then moves out of the ER, through the Golgi complex, where N- and O- (for Ii) linkage to glycans takes place. Ii is removed from class II after egress from the trans-Golgi apparatus to the cell surface by sequential COOH terminal proteolytic cleavage [33]. Ii contains a segment encoded by exon 3, which is termed class-H associated invariant chainderived peptide (CLIP). CLIP occupies the peptide binding groove of class II molecules in a manner that is indistinguishable from that of antigenic peptides. The CLIP region is essential for the transportation of class II from the ER [2 ].
6.
PEPTIDE GENERATION AND MHC ASSOCIATION
The first possible site of peptide binding by MHC-I is in the ER lumen. There are genes in the MHC complex coding for transporters associated with antigen processing (TAP-l, -2) [34,35,36]. Embryonic stem cells lack TAP transcripts. These transporters show size and chemical selectivity. Transportation is optimal with peptides approximately 12 residues in length. TAP are translocated into the ER lumen during transportation. Tapasin provides linkage between the nascent MHC-132M complex, the available peptide binding site and TAE This is important for the efficient loading of the peptide onto MHC-I. The antigenic peptide is generated in proteosomes, which is a large assembly of 16-20 components and is capable of degradation of proteins in the cytosol as part of housekeeping and of regulated functions of the cell [37,38]. Two proteosome subunits, LMP-1 and LMP-7, are encoded next to TAP-1 and TAP-2 in the MHC complex. The LMP proteins and the related MECL-1 are interferon-y (IFN-y) inducible [39,40,41,42]. The antigenic peptides presented by MHC-II are the result of endocytic proteolysis. The Ii (CLIP) chain occupies the peptide binding site of MHC-II and thus interferes with peptide binding in the ER lumen, preventing association with endogenous peptides [43,44]. Newly synthesized MHC-II molecules localize to unique endocytic vesicles distinct from typical endosomes where peptide loading takes place before expression at the cell surface [45,46,47,48]. Progressive proteolysis of the Ii chain by cathepsins within the endocytic pathway results in the in situ generation of MHC-II molecules with CLIP in their binding sites [49]. CLIP must be removed prior to binding the antigenic peptide. CLIP removal is mediated by a class-Hlike heterodimer, called DM, whose component chains are encoded within the MHC complex [50,51,52]. There is evidence to indicate that initially MHC-II captures large protein fragments just after unfolding in the endosomes, which are then digested while the fragment bound in the MHC-II groove is protected from degradation [53]. In most cases class-II antigen presentation is mediated by newly synthesized oc~ dimers, Ii and DM. However, there is also evidence for the internalization and recycling of mature class-II molecules through early endocytic compartments [54,55,56].
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HLA-DM catalyzes the exchange and selection of ligands for MHC class II molecules in mature endosomal/lysosomal compartments. DM edits peptides in early endosomes, and by this influences presentation by recycling class II molecules. Maximal class II-restricted presentation of an albumin-derived peptide by recycling class II molecules was observed in cells lacking HLA-DM. DM editing of this epitope was observed in early endocytic compartments as revealed by inhibitors of early to late endosomal transport. Editing was tempered by coexpression of HLA-DO [57]. Peptide occupancy controls the lifetime of cell surface MHC-II molecules. B lymphocytes use their surface immunoglobulin to bind and internalize antigen [58,59]. Macrophages and dendritic cells have receptors that recognize common features of pathogen antigens, such as mannose residues [60]. Non-B cells can also use antibodies to capture antigen via FcyRIII that triggers rapid endocytosis in macrophages [61]. There are also examples of presentation of "endogenous" antigens by MHC-II molecules [62].
7.
CYTOKINES AND ANTIGEN PRESENTATION
It is generally held that different subsets of T cells and cytokines are involved in the cellular and humoral immune response. Thl cells, which evoke cell-mediated immunity and phagocyte-dependent inflammation, produce interferon (IFN)-gamma, interleukin (IL)-2 and tumor necrosis factor (TNF)-beta. Th2 cells, which evoke strong antibody responses (including those of the IgE class) and eosinophil accumulation, but inhibit several functions of phagocytic ceils, produce IL-4, IL-5, IL-6, IL-9, IL- 10, and IL- 13 [63]. IL-15 has been implicated in the differentiation of Langerhans cells from monocytes [64]. ILl 3 is also an important regulatory factor involved in both early innate and late adaptive responses [65]. IL-10-treated DCs and, to a lesser extent, hydrocortisone (HC)-treated DCs showed a decreased expression of MHC-II molecules, the costimulatory molecule CD86, the DC-specific marker CD83 and IL-12 secretion is markedly reduced. As a result, T-cell proliferation was reduced after stimulation with either IL-10- or HC-treated DCs. However, IL-10 inhibited the production of both TH1 and TH2 cytokines, whereas HC inhibited the production of IFN 7, but increased the release of IL-4 and there was no change in IL-5. Both effects were long-lasting [66]. The expression of MHC-I is enhanced by IFN~/. In general, IFN7 slows the maturation rates of class I complexes and causes a prolonged retention of molecules in the ER, because it regulates the expression of ER-residing proteins during maturation. Consequently, IFN 7 induces more rigorous ER quality control [67]. Chemokines also participate in immune activation. Thus, TH1 reactions depend upon IFN Yinduced CXC chemokines: IFN- inducible protein (IP)-10, IFN-inducible T cell-alpha chemoattractant (iTAC) and monokine induced by IFN7 (MiG), which bind to chemokine receptor CXCR3. TH2 lymphocytes express the chemokine receptors CCR4 and CCR8 for which thymus- and activation-regulated chemokine (TARC), macrophage-derived chemokine (MDC) and 1-309 function as ligands, respectively [68].
8.
ANTIGEN PRESENTATION BY "NONCLASSICAL" MOLECULES
It is now emerging that in addition to the "classical" MHC-I and MHC-II, "non-classical" MHC molecules, such as Qa-2, also present antigen in both innate and adaptive immune responses,
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as well as participate in embryonic development [69]. In the eye B cells are necessary for
tolerogenic antigen presentation. Anterior chamber associated B cells do not directly suppress the expression of delayed-type hypersensitivity. Instead, antigen-specific regulatory T cells are induced by B cells that require the identity of histocompatibility antigens at the TL/Qa-1 region
[70]. Similarly, CD 1 molecules, a family of cell surface-associated glycoproteins, are now recognized as having a role in antigen presentation. These glycoproteins are distinct from, yet have some similarities to classical major histocompatibility complex class I and class II molecules. They can present nonprotein antigens to certain subpopulations of T cells [71 ]. CD 1d constitutes a carbohydrate antigen processing system enabling T cells to recognize processed fragments of complex glycolipids [72]. CD 1d molecules control the function of natural T cells, which are an early source of cytokines that stimulate type 1 or type 2 differentiation of helper T lymphocytes. CD 1d is postulated to sense alterations in cellular lipid content by virtue of its affinity for such ligands. The presentation of altered-self glycolipid, presumably after infectious assault of antigen-presenting cells, activates natural T cells, which promptly release pro-inflammatory and anti-inflammatory cytokines and jump-start the immune system [73]. Glycolipid-specific, CD 1a-, b- and c-dependent cytotoxic T cells have recently been shown to be involved in the host immunity against tuberculosis. These CD 1 molecules present mycobacterial glycolipids from different intracellular sites in the infected cell. CD 1d-dependent natural killer T cells promptly produce cytokines and perform regulatory activities [74]. Human histocompatibility leukocyte antigen (HLA)-G is an antigen-presenting molecule and down-modulates CD8(+) and CD4(+) T-cell responsiveness. HLA-G modulates innate immunity by interacting with immunoglobulin-like receptors and by regulating HLA-E expression and its interaction with CD94/NKG2 receptors [75].
9.
BIOLOGICAL SIGNIFICANCE OF ANTIGENIC PEPTIDE PRESENTATION
It is generally accepted that MHC presenting self-peptides are involved in the selection of the T cell repertoire in the thymus. In the periphery T cell regulatory and effector responses are dependent on MHC-peptide presentation. Some pathogens mimic self-antigens and thus escape immune attack. Such mimicry may also lead to the activation of autoimmune reactions. Continuous mutation of the antigens is another way by which pathogens escape immune attack. These mutations lead to epitope substitution and give advantage to the pathogen (e.g. in the case of HIV). Some mutations may lead to the loss of MHC binding of the peptide. Many pathogens have the ability to produce molecules that modulate the immune response [76]. Viruses have developed many ways to escape immune surveillance and to downregulate the immune response in their hosts. All the viruses that induce generalized immunosuppression appear to do so by hindering antigen presentation to T cells and/or hematopoiesis [77]. The diversity of MHC and of lymphocyte antigen receptors provides protection against the mutational evasion of antigen presentation. Intracellular pathogens produce proteins from which peptides are derived that enter the ER and are presented by MHC-I molecules. This presentation stimulates CD8+ T cells that differentiate into cytotoxic T lymphocytes capable of killing the infected target cells. CD8+ cells also produce cytokines, such as TNF-~ and IFN-y. Antibody production is not stimulated by MHC-Ipeptide complexes. Cytotoxic T cells of the CD4+ subset also exist and such cells contribute to host defence. However, their major function is related to the termination of immune reactions by
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inducing apoptosis of excess lymphocytes via the Fas-FasL pathway. Cytokines provide protection against pathogens (e.g. by inducing NO) but pathogens also use cytokines in order to sway the immune response to their advantage [2]. Extracellular debris that may contain foreign material is taken up endocytically by MHC-II bearing cells, processed and presented to CD4+ effector/regulatory cells, including those helping antibody production by B cells. The antibody response is especially useful for the neutralization of exotoxins. Antigen specific B cells are capable of recognizing the conformation of the antigen and form antibodies to conformational epitopes. Such antibodies are capable of recognizing proteins in their native folded state, which is of major significance from the point of view of fighting pathogenic microorganism. Pre-existing antibodies facilitate the uptake of antigen by macrophages and dendritic cells via Fcy receptors that promote endocytosis. Passively acquired maternal antibodies can compete for antigen and prevent antigen presentation by B lymphocytes [2]. The high-affinity IgG receptor (CD64 or FcyRI) is constitutively expressed exclusively on professional APC. When antigen is targeted specifically to FcyRI, presentation is markedly enhanced. FcyRI-targeted antigens converge upon a class I processing pathway. Such targeting can lead to Ag-specific activation of cytotoxic T cells [78]. B lymphocytes play an essential role as APC also for T cell expansion in lymph nodes and for systemic T cell responses to low concentrations of antigen [79]. B-cell interaction with antigens that are immobilized on the surface of a target cell leads to binding (the formation of a synapse) and the acquisition of membrane-integral antigens from the target. B-cell antigen receptor accumulates at the synapse, segregated from the CD45 co-receptor, which is excluded. B cells concentrate antigen by this mechanism and thereby potentiate antigen processing and presentation to T cells with high efficacy [80]. The indication is that B cell-deficient mice have a diminished IL-2 production and do not develop normal frequencies of memory cells after immunization. The transfer of B cells to such mice restored memory cell development. Antigen presentation was not essential for this function, since B cells activated in vitro with irrelevant antigen also restored the frequencies of memory cells [81 ]. The stimulation of antibody production by B-cells was observed in the presence of antigenpulsed macrophages. Similar levels of stimulation were detected following depletion of Thy 1.2(+) cells from spleen cell preparations. Stimulation was inhibited by antigen specific IgG antibodies. This B cell-macrophage interaction was mediated by MHC-II [82]. A new B7 family member, B7-DC, whose expression is highly restricted to DCs, was identified. B7-DC binds PD1, a receptor for B7-H1/PD-L1. B7-DC costimulates T cell proliferation more efficiently than does B7.1 and induces IFNy but not IL-4 or IL-10 production by isolated naive T cells. These properties of B7-DC may account for the ability of DC to initiate potent T helper cell type 1 responses [83]. Necrotic but not apoptotic cells release heat shock protein (HSP) gp96, calreticulin, hsp90 and hsp70. HSP stimulates cytokine secretion by macrophages and induces the expression of antigen-presenting and co-stimulatory molecules on the DC. HSP gp96 and hsp70 act differentially, and each induces some but not all molecules. HSP interacts with APC through the highly conserved NF~zB pathway. Normally HSP are intracellular, abundant and soluble. Their appearance in the extra-cellular milieu and the consequent activation of APC represents an effective immune mechanism for the handling of cell death. HSP are conserved from bacteria to mammals. Therefore, the ability of HSP to activate APC provides a unified mechanism for response to internal stimuli as well as to microbes [84]. Complexes of the heat shock protein, gp96, and antigenic peptides are taken up by antigen-
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presenting cells and presented by MHC class I molecules. The uptake of gp96 had been postulated to occur through a receptor, identified recently as CD91. Complexes of peptides with heat shock proteins hsp90, calreticulin, and hsp70 are also taken up by macrophages and dendritic cells and presented by MHC class I molecules. All heat shock proteins utilize the CD91 receptor. Processing of gp96-chaperoned peptides requires proteosomes and the transporters associated with the classical endogenous antigen presentation pathway [85]. The question how CD4+ T cells provide help to CD8+ T cell responses is not resolved. The most compelling model, which is based on in vivo observations, is that a single APC, most likely a dendritic cell, stimulates both CD4+ and CD8+ T cells by displaying antigenic epitopes associated by MHC-II and MHC-I respectively. The proximity allows for the interaction of CD4+ and CD8+ cells via cytokines, which leads to the initiation of cell mediated immunity [86]. There are indications that immune responses do not show exquisite specificity as it is generally assumed. Although singular TCR can discriminate as exquisitely among antigens as the most specific antibodies but also exhibit "degeneracy": i.e., it can react with many disparate antigens (peptide-MHC complexes). An explanation for this duality (specificity and degeneracy) can be found in: (i) The powerful amplifying signal transduction cascades that allow a T cell to respond to the stable engagement of very few TCR molecules, initially perhaps only one or two out of around 100,000 per cell, and (ii) The inverse relationship between TCR affinity for epitopes and epitope density. B cells also exhibit degeneracy, as well as specificity [87].
10.
CONCLUSIONS
The recent observations discussed here emphasizes further the importance of antigen presentation as a fundamental signal in immune function. It is now indicated that this signal is not only capable of initiating a response, but also determines the type of the response elicited. The concept of "tolerogenic" antigen presentation is novel and exciting, as are the indications that there are specialized APC molecules that would efficiently present carbohydrates or lipids. Another important finding is that there are APC molecules with capabilities of activating both the innate and the adaptive immune system and that natural immune T cells instantaneously produce cytokines in response to such APC that serve to "jump start" the specific immune system. Finally, the heat shock protein system serves as an ultimate example to illustrate what the immune system is about. The HSP system serves to eliminate dead cells from tissues under physiological or pathophysiological conditions and it fights microorganisms that may invade the host. Clearly our advanced understanding of antigen presentation reconfirms the dominant nature of this signal for immune function. The original extrapolations from antigen presentation that adherence signals are dominant in cell biology is well illustrated by these recent developments. The general validity of these signals as antigen and cell specific adherence signals that initiate immune reactions have been substantiated by more examples than ever before. The response to these signals, which seem now qualitatively different, may be immunity, tolerance, anergy and even lymphocyte death (apoptosis). Apparently, the signaling is dependent on the physiological (homeostatic) and pathological (allostatic) requirements in higher animals and in man [88,89]. Indeed, it is now emerging that APC adherence signals have major roles not only in governing the protection of the host, but also in the physiological and pathophysiological regulation of bodily functions.
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Edited by I. Berczi and A. Szentivanyi 9 2003 Elsevier Science B.V. All rights reserved
Antigen Presentation
ISTVAN BERCZI and ANDOR SZENTIVANYI
Department of Immunology, Faculty of Medicine, The University of Manitoba, Winnipeg, Manitoba R3E OW3, Canada; and Department of Internal Medicine, Faculty of Medicine, The University of South Florida, Tampa, Florida 33612, USA ABSTRACT Antigen presentation takes place by cell-to-cell interaction whereby a complex signaling process via cell surface adhesion molecules initiates the adaptive (antigen specific) immune responses. Without exception the macromolecular antigen undergoes proteolytic breakdown and peptide fractions (-~9-24 residues) are presented by antigen presenting cells (APC) in association with surface MHC antigens. External antigens are engulfed by phagocytic mononuclear cells and are digested in endosomes and the peptide fragments are joining with MHC-II molecules in endocytic vesicles (endocytic pathway of processing) prior to expression on the cell surface. The APC of this pathway are resposible for the induction of the antibody response and delayed type hypersensitivity reactions. Endogenous antigens are processed in the cytoplasm, in enzyme-containing proteosomes (cytosolic pathway) and the peptides generated are associated with MHC-I in the endoplsmic reticulum, which in turn is expressed on the surface of all nucleated cells in the body. Cytotoxic T lymphocytes recognize MHC-I-peptide complexes on the cell surface and destroy infected and cancer cells. This antigen presenting system requires the digestion of the antigen after phagocytosis, which protects against extracellular and intracellular pathogens, it exposes hidden antigenic determinents, decreases the impact of mutations by employing short peptides and allows for self-non-self discrimination. Non-classical MHC antigens are also involved in antigen presentation and specialized surface molecules (CD1) mediate carbohydrate and lipid presentation. Heat shock proteins normally serve to eliminate dead cells from tissues but also form complexes with antigen which are taken up by APC through a specific receptor (CD91). Such complexes are taken up by macrophages and dendritic cells, digested and are presented by MHC-I. The dominant role of antigen presentation in the adaptive immune system illustrates the fundamental regulatory function of adherence signals in multi-cellular organisms.
1.
INTRODUCTION
Adaptive immune reactions are mediated by lymphocyte clones that have specific receptors for the determinants (epitopes) of the antigen. Initially, the antigen was assumed to be the sole signal that instructed immunocytes to make antibodies by some sort of recognizing and copying mechanism [ 1]. Later it was realized that antibody specificity is genetically coded and that the antigen has to be digested and presented by specialized antigen presenting cells (APC) to T lyre-
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phocytes. Phagocytic mononuclear cells (monocyte-macrophages), B lymphocytes and some specialized cells (e.g., dendritic cells, Langerhans cells, Kuppfer cells) are "professional" APC that present antigen via major histocompatibility (MHC)-I and MHC-II. In the central nervous system the macrophage-related microglia and to a lesser extent, astrocytes, are involved in antigen presentation as well as in inflammatory responses. However, all nucleated cells are capable of antigen presentation by MHC-I, which is constitutively expressed by such cells. In addition, IFNy is capable of inducing the expression of MHC-II in somatic cells, which enables them to present antigens by this pathway. Major histocompatibility antigens bind peptides during their intracellular biosynthesis and carry them to the surface of APC. In turn the digested (processed) antigenic peptide-MHC complexes are recognized by T cells as "altered self" [2,3,4,5,6]. The conventional view is that the T cell receptor recognizes the MHC antigen as "self" and the peptide as "non-self' in this process. This self-nonself recognition has evolved to provide protection against autoimmune reactions while foreign invaders are attacked. The requirement for T cells to recognize antigens in the context of MHC assures that infected and cancerous cells are specifically eliminated by killer cells. However, soluble antigen, which is not processed and not associated with MHC antigens, is not capable of triggering killer T lymphocytes. This mechanism prevents the exhaustion of T cells by viremia or by other antigen that is present in the circulation [2]. 2.
THE SIGNIFICANCE OF PROCESSING
The requirement for processing has several advantages: (i) It involves the phagocytosis and digestion of the antigen, which leads to inactivation of microbes, viruses and other pathogens; (ii) Digestion and presentation allow for the presentation of epitopes from the antigens of intracellular pathogens to T cells. This leads to the selective elimination of infected or cancerous cells. (iii) Epitopes that are hidden in the native molecule, viruses etc. may be recognized after processing and presentation; (iv) It reduces the chance of avoiding recognition by mutation of the antigen; (v) It allows for self-nonself discrimination [2].
3.
ANTIGEN RECOGNITION BY T CELLS
The current consensus is that T lymphocytes recognize self-MHC antigens via their receptors (TCR). During the development of T cells, those clones that are triggered for an immune response by self-MHC are killed (selected out) in the thymus and also in the periphery. The cells that remain "recognize", but are not activated by self-MHC. The various clones will, however, be activated if the MHC molecule contains a peptide fragment for which the T cell clone shows specificity. The TCR of these cells recognizes the peptide antigen in the "context" of self-MHC as "altered self". This phenomenon is known as the MHC-restriction of T-cell activation. If the MHC component is missing, the T cell will not be activated. MHC-II presents antigens to CD4+ and MHC-I to CD8+ T cells. CD4 and CD8 are accessory recognition molecules on the surface of these T cells, which contribute to MHC recognition by the T lymphocyte. These rules apply to a[3TCR [71. MHC-II is involved in the presentation of foreign antigen-derived peptides. This is called the endocytic pathway as the antigens are ingested by endocytosis, digested and the resulting peptides presented by APC to T cells. MHC-I presents peptides by the cytosolic pathway, which are derived from the cytosol of the cell itself. While the endocytic pathway is present
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only in specialized APC, the cytosolic pathway is present in all cells of the body, as MHC-I is expressed by all somatic cells. This latter pathway serves the purpose of immunological surveillance against intracellular pathogens (e.g., viruses, some bacteria, protozoa and fungi) and cancer. CD8+ cytotoxic T lymphocytes patrol the entire body by penetrating the tissues via the high endothelial cells in capillaries and detect and kill abnormal cells expressing altered MHC-I antigens [2,3,4].
4.
PEPTIDE BINDING BY MHC
In the MHC-I molecule the ~1 and ~2 domains combine to form a single peptide binding site supported by a l]-pleated sheet floor containing eight strands bound by two ~ helices, one from ~1 and the other from ~2. I]2-microglobulin makes contact with the immunoglobulin-like ~3 domain and also with the ~ sheet floor of the ~1~2 peptide-binding region. These structures show a series of pockets studding the peptide-binding groove. Occasionally the pockets extend deep between the floor and helical walls of the binding domain [8,9,10,11]. These pockets have now been designated from A to F. MHC polymorphism is primarily related to the diversification of their peptide-binding specificities. Different alleles are meant to bind distinct sets of peptides. Hydrogen bonds, hydrophobic interactions, and generic sequence independent interactions play major roles in peptide binding. MHC molecule polymorphism directly influences recognition by TCR. Distinct alleles of MHC molecules bind and present distinct peptides to T lymphocytes [9,10,12,13]. The interaction of peptides with MHC-I is very stable and the peptides bound are of fixed length of mostly 9 (8-10) amino acids. Predominant amino acids are found in comparable positions, which are called motif or anchor amino acids, that promote binding to a particular allele of MHC-I. Most peptides presented by MHC-I are derived from cytoplasmic or nuclear proteins. Physiologically stable class I molecules are actually trimers of the MHC heavy chain, ~2-microglobulin and the peptide. These components synergize in forming a long-lived, properly-folded complex [ 15,16,17]. MHC-II bound peptides are longer and more heterogeneous in size, ranging from 12 to more than 24 residues. Anchor residues play a role in binding. These peptides are derived from proteins that have access to the endocytic pathway of antigen processing. Intracellular proteins access the class II pathway inefficiently compared with the class-I pathway, although exceptions have been reported. For class-II molecules the peptide is not needed for the maintenance of chain association at physiologic temperature and pH. MHC-II molecules bind peptides mostly via main chain atoms and not by the ends of the peptide [ 18,19,20,21 ].
5.
SYNTHESIS OF MHC-I AND MHC-II
Class-I MHC and ~2-microglobulin (~2M) are type I proteins and enter the endoplasmic reticulum (ER) via the signal recognition and transport apparatus. The MHC chain associates rapidly with an ER resident protein now termed calnexin [22]. This protein is Ca 2+sensitive and is associated with the signal sequence dependent translocation apparatus and interacts with various membrane and secreted proteins in ER. Calnexin's binding to the MHC-I chain involves both carbohydrate and protein structure recognition [23,24]. In the case of human MHC-I, this chaperone dissociates from the molecule upon binding [~2M and another chaperone, calreticulin, will
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combine with the complex [25]. At this stage the MHC-132M complex also associates with an MHC-encoded molecule called tapasin [26]. Once the MHC-~32M complex is associated with the antigenic peptide, calreticulin and tapasin dissociate from the complex, which exits the ER and moves through the Golgi network on to the cell surface by the default secretory pathway. MHC class II a and 13 chains associate soon after synthesis in the presence of the invariant chain (Ii), which is a nonpolymorphic type II membrane glycoprotein [27,28]. Ii is a family of proteins. Ii forms noncovalently associated trimes in ER, and Class II a~ dimers are quickly associate with such trimers [29,30]. Non-class II associated Ii binds to calnexin, which dissociates upon the formation of class II-Ii oligomers [31,32]. The c~[3Ii complex then moves out of the ER, through the Golgi complex, where N- and O- (for Ii) linkage to glycans takes place. Ii is removed from class II after egress from the trans-Golgi apparatus to the cell surface by sequential COOH terminal proteolytic cleavage [33]. Ii contains a segment encoded by exon 3, which is termed class-H associated invariant chainderived peptide (CLIP). CLIP occupies the peptide binding groove of class II molecules in a manner that is indistinguishable from that of antigenic peptides. The CLIP region is essential for the transportation of class II from the ER [2 ].
6.
PEPTIDE GENERATION AND MHC ASSOCIATION
The first possible site of peptide binding by MHC-I is in the ER lumen. There are genes in the MHC complex coding for transporters associated with antigen processing (TAP-l, -2) [34,35,36]. Embryonic stem cells lack TAP transcripts. These transporters show size and chemical selectivity. Transportation is optimal with peptides approximately 12 residues in length. TAP are translocated into the ER lumen during transportation. Tapasin provides linkage between the nascent MHC-132M complex, the available peptide binding site and TAE This is important for the efficient loading of the peptide onto MHC-I. The antigenic peptide is generated in proteosomes, which is a large assembly of 16-20 components and is capable of degradation of proteins in the cytosol as part of housekeeping and of regulated functions of the cell [37,38]. Two proteosome subunits, LMP-1 and LMP-7, are encoded next to TAP-1 and TAP-2 in the MHC complex. The LMP proteins and the related MECL-1 are interferon-y (IFN-y) inducible [39,40,41,42]. The antigenic peptides presented by MHC-II are the result of endocytic proteolysis. The Ii (CLIP) chain occupies the peptide binding site of MHC-II and thus interferes with peptide binding in the ER lumen, preventing association with endogenous peptides [43,44]. Newly synthesized MHC-II molecules localize to unique endocytic vesicles distinct from typical endosomes where peptide loading takes place before expression at the cell surface [45,46,47,48]. Progressive proteolysis of the Ii chain by cathepsins within the endocytic pathway results in the in situ generation of MHC-II molecules with CLIP in their binding sites [49]. CLIP must be removed prior to binding the antigenic peptide. CLIP removal is mediated by a class-Hlike heterodimer, called DM, whose component chains are encoded within the MHC complex [50,51,52]. There is evidence to indicate that initially MHC-II captures large protein fragments just after unfolding in the endosomes, which are then digested while the fragment bound in the MHC-II groove is protected from degradation [53]. In most cases class-II antigen presentation is mediated by newly synthesized oc~ dimers, Ii and DM. However, there is also evidence for the internalization and recycling of mature class-II molecules through early endocytic compartments [54,55,56].
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HLA-DM catalyzes the exchange and selection of ligands for MHC class II molecules in mature endosomal/lysosomal compartments. DM edits peptides in early endosomes, and by this influences presentation by recycling class II molecules. Maximal class II-restricted presentation of an albumin-derived peptide by recycling class II molecules was observed in cells lacking HLA-DM. DM editing of this epitope was observed in early endocytic compartments as revealed by inhibitors of early to late endosomal transport. Editing was tempered by coexpression of HLA-DO [57]. Peptide occupancy controls the lifetime of cell surface MHC-II molecules. B lymphocytes use their surface immunoglobulin to bind and internalize antigen [58,59]. Macrophages and dendritic cells have receptors that recognize common features of pathogen antigens, such as mannose residues [60]. Non-B cells can also use antibodies to capture antigen via FcyRIII that triggers rapid endocytosis in macrophages [61]. There are also examples of presentation of "endogenous" antigens by MHC-II molecules [62].
7.
CYTOKINES AND ANTIGEN PRESENTATION
It is generally held that different subsets of T cells and cytokines are involved in the cellular and humoral immune response. Thl cells, which evoke cell-mediated immunity and phagocyte-dependent inflammation, produce interferon (IFN)-gamma, interleukin (IL)-2 and tumor necrosis factor (TNF)-beta. Th2 cells, which evoke strong antibody responses (including those of the IgE class) and eosinophil accumulation, but inhibit several functions of phagocytic ceils, produce IL-4, IL-5, IL-6, IL-9, IL- 10, and IL- 13 [63]. IL-15 has been implicated in the differentiation of Langerhans cells from monocytes [64]. ILl 3 is also an important regulatory factor involved in both early innate and late adaptive responses [65]. IL-10-treated DCs and, to a lesser extent, hydrocortisone (HC)-treated DCs showed a decreased expression of MHC-II molecules, the costimulatory molecule CD86, the DC-specific marker CD83 and IL-12 secretion is markedly reduced. As a result, T-cell proliferation was reduced after stimulation with either IL-10- or HC-treated DCs. However, IL-10 inhibited the production of both TH1 and TH2 cytokines, whereas HC inhibited the production of IFN 7, but increased the release of IL-4 and there was no change in IL-5. Both effects were long-lasting [66]. The expression of MHC-I is enhanced by IFN~/. In general, IFN7 slows the maturation rates of class I complexes and causes a prolonged retention of molecules in the ER, because it regulates the expression of ER-residing proteins during maturation. Consequently, IFN 7 induces more rigorous ER quality control [67]. Chemokines also participate in immune activation. Thus, TH1 reactions depend upon IFN Yinduced CXC chemokines: IFN- inducible protein (IP)-10, IFN-inducible T cell-alpha chemoattractant (iTAC) and monokine induced by IFN7 (MiG), which bind to chemokine receptor CXCR3. TH2 lymphocytes express the chemokine receptors CCR4 and CCR8 for which thymus- and activation-regulated chemokine (TARC), macrophage-derived chemokine (MDC) and 1-309 function as ligands, respectively [68].
8.
ANTIGEN PRESENTATION BY "NONCLASSICAL" MOLECULES
It is now emerging that in addition to the "classical" MHC-I and MHC-II, "non-classical" MHC molecules, such as Qa-2, also present antigen in both innate and adaptive immune responses,
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as well as participate in embryonic development [69]. In the eye B cells are necessary for
tolerogenic antigen presentation. Anterior chamber associated B cells do not directly suppress the expression of delayed-type hypersensitivity. Instead, antigen-specific regulatory T cells are induced by B cells that require the identity of histocompatibility antigens at the TL/Qa-1 region
[70]. Similarly, CD 1 molecules, a family of cell surface-associated glycoproteins, are now recognized as having a role in antigen presentation. These glycoproteins are distinct from, yet have some similarities to classical major histocompatibility complex class I and class II molecules. They can present nonprotein antigens to certain subpopulations of T cells [71 ]. CD 1d constitutes a carbohydrate antigen processing system enabling T cells to recognize processed fragments of complex glycolipids [72]. CD 1d molecules control the function of natural T cells, which are an early source of cytokines that stimulate type 1 or type 2 differentiation of helper T lymphocytes. CD 1d is postulated to sense alterations in cellular lipid content by virtue of its affinity for such ligands. The presentation of altered-self glycolipid, presumably after infectious assault of antigen-presenting cells, activates natural T cells, which promptly release pro-inflammatory and anti-inflammatory cytokines and jump-start the immune system [73]. Glycolipid-specific, CD 1a-, b- and c-dependent cytotoxic T cells have recently been shown to be involved in the host immunity against tuberculosis. These CD 1 molecules present mycobacterial glycolipids from different intracellular sites in the infected cell. CD 1d-dependent natural killer T cells promptly produce cytokines and perform regulatory activities [74]. Human histocompatibility leukocyte antigen (HLA)-G is an antigen-presenting molecule and down-modulates CD8(+) and CD4(+) T-cell responsiveness. HLA-G modulates innate immunity by interacting with immunoglobulin-like receptors and by regulating HLA-E expression and its interaction with CD94/NKG2 receptors [75].
9.
BIOLOGICAL SIGNIFICANCE OF ANTIGENIC PEPTIDE PRESENTATION
It is generally accepted that MHC presenting self-peptides are involved in the selection of the T cell repertoire in the thymus. In the periphery T cell regulatory and effector responses are dependent on MHC-peptide presentation. Some pathogens mimic self-antigens and thus escape immune attack. Such mimicry may also lead to the activation of autoimmune reactions. Continuous mutation of the antigens is another way by which pathogens escape immune attack. These mutations lead to epitope substitution and give advantage to the pathogen (e.g. in the case of HIV). Some mutations may lead to the loss of MHC binding of the peptide. Many pathogens have the ability to produce molecules that modulate the immune response [76]. Viruses have developed many ways to escape immune surveillance and to downregulate the immune response in their hosts. All the viruses that induce generalized immunosuppression appear to do so by hindering antigen presentation to T cells and/or hematopoiesis [77]. The diversity of MHC and of lymphocyte antigen receptors provides protection against the mutational evasion of antigen presentation. Intracellular pathogens produce proteins from which peptides are derived that enter the ER and are presented by MHC-I molecules. This presentation stimulates CD8+ T cells that differentiate into cytotoxic T lymphocytes capable of killing the infected target cells. CD8+ cells also produce cytokines, such as TNF-~ and IFN-y. Antibody production is not stimulated by MHC-Ipeptide complexes. Cytotoxic T cells of the CD4+ subset also exist and such cells contribute to host defence. However, their major function is related to the termination of immune reactions by
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inducing apoptosis of excess lymphocytes via the Fas-FasL pathway. Cytokines provide protection against pathogens (e.g. by inducing NO) but pathogens also use cytokines in order to sway the immune response to their advantage [2]. Extracellular debris that may contain foreign material is taken up endocytically by MHC-II bearing cells, processed and presented to CD4+ effector/regulatory cells, including those helping antibody production by B cells. The antibody response is especially useful for the neutralization of exotoxins. Antigen specific B cells are capable of recognizing the conformation of the antigen and form antibodies to conformational epitopes. Such antibodies are capable of recognizing proteins in their native folded state, which is of major significance from the point of view of fighting pathogenic microorganism. Pre-existing antibodies facilitate the uptake of antigen by macrophages and dendritic cells via Fcy receptors that promote endocytosis. Passively acquired maternal antibodies can compete for antigen and prevent antigen presentation by B lymphocytes [2]. The high-affinity IgG receptor (CD64 or FcyRI) is constitutively expressed exclusively on professional APC. When antigen is targeted specifically to FcyRI, presentation is markedly enhanced. FcyRI-targeted antigens converge upon a class I processing pathway. Such targeting can lead to Ag-specific activation of cytotoxic T cells [78]. B lymphocytes play an essential role as APC also for T cell expansion in lymph nodes and for systemic T cell responses to low concentrations of antigen [79]. B-cell interaction with antigens that are immobilized on the surface of a target cell leads to binding (the formation of a synapse) and the acquisition of membrane-integral antigens from the target. B-cell antigen receptor accumulates at the synapse, segregated from the CD45 co-receptor, which is excluded. B cells concentrate antigen by this mechanism and thereby potentiate antigen processing and presentation to T cells with high efficacy [80]. The indication is that B cell-deficient mice have a diminished IL-2 production and do not develop normal frequencies of memory cells after immunization. The transfer of B cells to such mice restored memory cell development. Antigen presentation was not essential for this function, since B cells activated in vitro with irrelevant antigen also restored the frequencies of memory cells [81 ]. The stimulation of antibody production by B-cells was observed in the presence of antigenpulsed macrophages. Similar levels of stimulation were detected following depletion of Thy 1.2(+) cells from spleen cell preparations. Stimulation was inhibited by antigen specific IgG antibodies. This B cell-macrophage interaction was mediated by MHC-II [82]. A new B7 family member, B7-DC, whose expression is highly restricted to DCs, was identified. B7-DC binds PD1, a receptor for B7-H1/PD-L1. B7-DC costimulates T cell proliferation more efficiently than does B7.1 and induces IFNy but not IL-4 or IL-10 production by isolated naive T cells. These properties of B7-DC may account for the ability of DC to initiate potent T helper cell type 1 responses [83]. Necrotic but not apoptotic cells release heat shock protein (HSP) gp96, calreticulin, hsp90 and hsp70. HSP stimulates cytokine secretion by macrophages and induces the expression of antigen-presenting and co-stimulatory molecules on the DC. HSP gp96 and hsp70 act differentially, and each induces some but not all molecules. HSP interacts with APC through the highly conserved NF~zB pathway. Normally HSP are intracellular, abundant and soluble. Their appearance in the extra-cellular milieu and the consequent activation of APC represents an effective immune mechanism for the handling of cell death. HSP are conserved from bacteria to mammals. Therefore, the ability of HSP to activate APC provides a unified mechanism for response to internal stimuli as well as to microbes [84]. Complexes of the heat shock protein, gp96, and antigenic peptides are taken up by antigen-
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presenting cells and presented by MHC class I molecules. The uptake of gp96 had been postulated to occur through a receptor, identified recently as CD91. Complexes of peptides with heat shock proteins hsp90, calreticulin, and hsp70 are also taken up by macrophages and dendritic cells and presented by MHC class I molecules. All heat shock proteins utilize the CD91 receptor. Processing of gp96-chaperoned peptides requires proteosomes and the transporters associated with the classical endogenous antigen presentation pathway [85]. The question how CD4+ T cells provide help to CD8+ T cell responses is not resolved. The most compelling model, which is based on in vivo observations, is that a single APC, most likely a dendritic cell, stimulates both CD4+ and CD8+ T cells by displaying antigenic epitopes associated by MHC-II and MHC-I respectively. The proximity allows for the interaction of CD4+ and CD8+ cells via cytokines, which leads to the initiation of cell mediated immunity [86]. There are indications that immune responses do not show exquisite specificity as it is generally assumed. Although singular TCR can discriminate as exquisitely among antigens as the most specific antibodies but also exhibit "degeneracy": i.e., it can react with many disparate antigens (peptide-MHC complexes). An explanation for this duality (specificity and degeneracy) can be found in: (i) The powerful amplifying signal transduction cascades that allow a T cell to respond to the stable engagement of very few TCR molecules, initially perhaps only one or two out of around 100,000 per cell, and (ii) The inverse relationship between TCR affinity for epitopes and epitope density. B cells also exhibit degeneracy, as well as specificity [87].
10.
CONCLUSIONS
The recent observations discussed here emphasizes further the importance of antigen presentation as a fundamental signal in immune function. It is now indicated that this signal is not only capable of initiating a response, but also determines the type of the response elicited. The concept of "tolerogenic" antigen presentation is novel and exciting, as are the indications that there are specialized APC molecules that would efficiently present carbohydrates or lipids. Another important finding is that there are APC molecules with capabilities of activating both the innate and the adaptive immune system and that natural immune T cells instantaneously produce cytokines in response to such APC that serve to "jump start" the specific immune system. Finally, the heat shock protein system serves as an ultimate example to illustrate what the immune system is about. The HSP system serves to eliminate dead cells from tissues under physiological or pathophysiological conditions and it fights microorganisms that may invade the host. Clearly our advanced understanding of antigen presentation reconfirms the dominant nature of this signal for immune function. The original extrapolations from antigen presentation that adherence signals are dominant in cell biology is well illustrated by these recent developments. The general validity of these signals as antigen and cell specific adherence signals that initiate immune reactions have been substantiated by more examples than ever before. The response to these signals, which seem now qualitatively different, may be immunity, tolerance, anergy and even lymphocyte death (apoptosis). Apparently, the signaling is dependent on the physiological (homeostatic) and pathological (allostatic) requirements in higher animals and in man [88,89]. Indeed, it is now emerging that APC adherence signals have major roles not only in governing the protection of the host, but also in the physiological and pathophysiological regulation of bodily functions.
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