Immunoregulation

John J OShea, National Institutes of Health, Bethesda, Maryland, USA Thomas B Nutman, National Institutes of Health, Bethesda, Maryland, USA
The immune system serves essential functions in protection from numerous pathogenic organisms and, in general, is not harmful to the host. The process by which the immune response is restrained or controlled is termed immunoregulation. A number of different aspects of the immune system contribute to this process of immunoregulation, some of the most important being signals from antigen-presenting cells by costimulatory molecules, the effects of cytokines and apoptotic cell death.

Introductory article
Article Contents
. Introduction . Physiological Immunoregulation . Immunoregulation in Infectious, Allergic Autoimmune Disease and Immunodeficiency . Summary

Introduction
Immune responses are essential in providing protection from infectious organisms such as bacteria, viruses and parasites. Not surprisingly, the immune response is nely tuned to respond rapidly and appropriately to these agents. However, not only must the response be turned on quickly, but, equally important, it must be turned o eectively to prevent the harmful eects of an unchecked immune response. Thus, there are many steps at which the immune response is regulated. From the initial phases in which lymphocytes encounter antigen to the waning of the immune response after an infection, there is a variety of steps during the immune response that are targets for control; like many other systems in the body, homeostasis of the immune response is of great importance. Not only must the immune response to exogenously delivered antigens be controlled, but the immune response to self antigens also must be constrained or turned o. Therefore, a fundamental feature of the immune system is the lack of responsiveness to self antigens. This unresponsive state is termed tolerance. Although we do not have a full understanding of this process, recent advances in elucidating the molecular basis of immunoregulation have provided additional insights into how tolerance may be achieved. The fundamental step in the specic immune response, namely how lymphocytes develop and what they see as foreign (compared to self), is governed by processes known as positive and negative selection. For T cells this occurs primarily in the thymus. Self-reactive lymphocytes are eliminated by negative selection, also termed clonal deletion, and genetic determinants such as major histocompatability complex (MHC) molecules and T-cell receptor (TCR) molecules, are key elements. The elimination of self-reactive lymphocytes in the thymus is denoted as central tolerance. Lymphocyte selection, although exceedingly important, will not be discussed further in this article. Other critical means by which the immune response is controlled include: signalling by antigen, inhibitory and

costimulatory receptors, cytokines and cell death (Figure 1 and Table 1). These mechanisms contribute to what has been termed peripheral tolerance and will be the major focus of this article. Many of these processes apply to both T and B cells, but in general the events in T cells are better characterized and will be emphasized. How these regulatory mechanisms contribute to protection from infectious organisms and what occurs when there is a failure of immunological regulation will be considered, as will new therapeutic approaches based on immunoregulatory principles.

Physiological Immunoregulation
Lymphocyte activation: antigen receptors, inhibitory receptors and costimulatory molecules
Recognition of foreign antigen by lymphocytes initiates a cascade of biochemical steps that lead to cellular activation. In contrast, variant peptide antigens that bind T-cell antigen receptors less well do not fully activate lymphocytes, leading to partial activation and altered substrate phosphorylation. These peptides are termed altered peptide ligands and can cause anergy or nonresponsiveness of T cells. A specialized motif found in several immune receptors and in antigen receptors is the immunoreceptor tyrosinebased activation motif (ITAM), which serves to recruit other tyrosine kinases. Importantly, in addition to activating receptors, a number of immune inhibitory receptors have been identied. Instead of ITAMs, these receptors have immunoreceptor tyrosine-based inhibitory motifs (ITIMs) which recruit tyrosine phosphatases. Such receptors were rst recognized in natural killer (NK) and B cells, but are also expressed in T cells and macrophages. This is one way in which activation through antigen receptors on lymphocytes is carefully regulated.
1

ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / [Link]

Immunoregulation

Cytokines + T cell B7 +
Activation TCRMHC interaction APC CD28B7 interaction Cytokine production: Activation of TH1, IFN, IL-12, TH2, IL-4, IL-5 Inhibition of IL-10, TGF

(a)

CD28 Cytokines

Anergy No costimulation by CD28B7 interaction

(b)

Inhibition CTLA4B7 interaction

(c)

CTLA4

Fas FasL
Death

T cell (d)

T cell

Figure 1 Mechanisms that regulate immune responses. (a) Foreign antigens are presented to T cells by antigen-presenting cells (APCs) such as macrophages, B cells and dendritic cells. T cells recognize foreign antigen by virtue of their clonotypic T-cell antigen receptors (TCRs). Occupancy of the TCR initiates a series of biochemical events that lead to activation of T cells; however, the T cells are not fully activated unless they also receive signals from costimulatory molecules like CD28, which binds to B7 molecules on APCs. When fully activated, T cells produce cytokines, some of which enhance inflammatory and immune responses whereas others inhibit. Still others regulate the type of immune response, promoting allergic or cell-mediated responses. (b) If T cells do not receive signals from CD28, and if they are unable to produce and respond to cytokines, they may become anergic or nonresponsive. (c) In addition, after activation T cells upregulate another molecule, cytotoxic T lymphocyte-associated antigen 4 (CTLA4) which also binds B7 molecules, in contrast to CD28, CTLA4 transmits signals that inhibit lymphocyte activation. (d) When activated, T cells also express the molecules Fas and Fas ligand (FasL). Interaction of these molecules causes lymphocytes to undergo apoptotic cell death, thus constraining immune responses. Lymphocytes can also die because of the lack of cytokines; this is termed cytokine withdrawal apoptosis. IFN, interferon; IL, interleukin; MHC, major histocompatibility complex; TGF, transforming growth factor; TH, T helper cell.

Importantly, though, signals from antigen receptors are not sucient to activate lymphocytes. Recall that T cells only bind antigens that are presented by other cells. Thus, another key aspect of T-cell activation is engagement of molecules on the surface of the antigen-presenting cell (APC), called costimulatory molecules. Increasingly it is being recognized that APCs, such as dendritic cells, have pivotal roles in activating or tolerizing lymphocytes. Among the best characterized molecules in this category are members of the B7 family (B7-1 (CD80), and B7-2
2

(CD86)). These molecules can be upregulated by infectious organisms and by cytokines; engagement of B7-1 and B7-2 by a counterreceptor on T cells, CD28, greatly enhances activation signals. Signicantly, activation of T cells without a costimulatory signal can lead to anergy. Clonal anergy, then, in addition to clonal deletion is another means to achieve nonresponsiveness or tolerance to a given antigen. It has long been recognized that if adjuvants substances that elicit inammation (such as mycobacterial

ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / [Link]

Immunoregulation

Table 1 Major mechanisms involved in immunoregulation Mechanism Antigen receptor signalling Inhibitory receptors Costimulatory molecules on antigen-presenting cell B7/CD28 B7/CTLA4 Cytokines Apoptosis Eect Positive Negative Comment Activates kinases Altered peptides can inhibit signalling Bind phosphatases Upregulated by inammation T-cell counterreceptor CD28 CTLA-4 T-cell counterreceptor upregulated by activation; also binds B7 Numerous Two forms: cytokine withdrawal and activation-induced cell death

Positive Inhibitory Positive or negative Inhibitory

CTLA4, cytotoxic lymphocyte-associated antigen 4.

cell wall constituents) are coadministered with antigen, a vigorous immune response is elicited. It is now clear that adjuvants increase the expression of costimulatory molecules on APCs, permitting full lymphocyte activation. Inammation can thus provide a danger signal to the immune system, communicating the threat of pathogenic challenge to lymphocytes. Conversely, in the absence of inammation, antigen may be presented to T cells by cells with poor expression of costimulatory molecules; this may lead to anergy of the T cells. It should be noted that there is also a second T-cell counterreceptor for B7-1 and B7-2 called cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). In contrast to CD28, CTLA-4 transmits signals that inhibit lymphocyte activation, providing a pathway of classical feedback inhibition. Costimulation can work by activating both APCs and lymphocytes. An example of this is CD40 (on APCs) and CD40 ligand (on activated T cells). In summary, lymphocytes have antigen receptors that transmit activation signals, but full activation requires the engagement of costimulatory molecules; in their absence lymphocytes may be anergized. This may be one mechanism for extrathymic or peripheral tolerance. In addition, antagonizing activation signals are the signals provided by inhibitory receptors. Thus, even at the earliest steps in lymphocyte activation, there are opposing signals that constrain activation.

Cytokines involved in innate immunity and inflammation The major proinammatory cytokines include: interferon (IFN) a/b, interleukin (IL)1, tumour necrosis factor (TNF) a, TNFb or lymphotoxin (LT), IL-6 and the chemokines. Interferons inhibit viral replication and cellular proliferation, upregulate major histocompatibility complex (MHC) class I and downregulate of class II expression. IL-1 is a major inammatory cytokine whose principal eects are: the induction of fever, acute-phase protein synthesis and cachexia (wasting). It also induces production of other cytokines including: TNFa, IL-6 and chemokines. It is induced by lipopolysaccharide, TNFa and IL-1 itself. The actions of TNFa are similar, in some respects, to those of IL-1 and include: induction of fever, hypoglycaemia, cachexia and the acute-phase response in the liver; activation of the coagulation system; and increased adhesion of cells to endothelium. TNFa also causes depression of cardiac contractility and reduction of vascular resistance and, as such, is the major mediator of septic shock. Furthermore, it upregulates MHC class I expression, activates phagocytes and induces mononuclear phagocytes to produce cytokines such as IL-1, IL-6 and chemokines. A factor closely related to TNFa is lymphotoxin (LT; also called TNFb), which competes with TNFa for binding to the same receptors. As expected, LT has many of the same eects as TNFa but, in addition, it can bind to another protein, LTb, to form a cell surface complex. LTb knockout mice have severe disruption of lymph node architecture, indicating that LT and LTb have important [Link],likeTNFa, is encoded within the MHC and is produced by activated T cells (see below). Another major inammatory cytokine is IL-6, which acts on the liver to induce production of the acutephase proteins (C-reactive protein, serum amyloid A,
3

Cytokines
After foreign antigens presented by activated APCs have initiated lymphocyte activation, the lymphocytes in turn begin to produce soluble factors termed cytokines or interleukins. These are factors that act on lymphocytes and other cells and thus are major regulators of the immune response.

ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / [Link]

Immunoregulation

TH0

Th0

TH1

IL-12

IL-4

TH2

Th1 IL-2 LT IFN

Th2

IL-10 IL-4

IL-5

Eosinophil Macrophage B cell

Figure 2 Immunoregulation and the TH1 TH2 paradigm. Undifferentiated helper T cells (TH0) only produce interleukin (IL)-2. IL-12, produced by macrophages in response to pathogens, drives TH1 differentiation. In conjunction with IL-18, IL-12 causes interferon (IFN) g production, which further activates monocytes. When differentiated, TH1 cells produce IL-2, IFNg and lymphotoxin (LT). Among their actions, these cytokines serve to activate macrophages further. In contrast, TH2 cells produce IL-4, IL-5 and IL-10. IL-4 inhibits macrophage activation, causes class switching so that B cells produce immunoglobulin E, and is a growth factor for mast cells. IL-5 activates eosinophils and IL-10 inhibits immune responses.

a2-macroglobulin and brinogen) and to decrease synthesis of albumin and transferrin. In addition, IL-6 is a growth and dierentiation factor for B cells. IL-6 is produced by a variety of cells including mononuclear phagocytes in response to IL-1 and TNFa. Chemokines are a large family of chemotactic cytokines, which attract various types of leucocytes including T cells, neutrophils and mononuclear cells. Immunoregulatory cytokines The major immunoregulatory cytokines include: IFNg, IL-2, IL-4, IL-5, IL-10, IL-12, IL-13, IL-15 and IL-18. These cytokines can dramatically aect not only the strength of the immune response but also its character. Differentiation of T helper cells types 1 and 2 A critical concept that has emerged is that precursor CD4 1 or helper T cells dierentiate to one of two eector phenotypes (Figure 2). In mice, T helper type 1 (TH1) cells drive the immune response towards a cell-mediated
4

immune response whereas T helper type 2 (TH2) cells promote a humoral or allergic response. TH1 cells produce IL-2, LT (TNFb) and IFNg, whereas TH2 cells produce IL4, IL-5 and IL-13. As discussed below, TH1 responses are important for clearing the majority of dierent types of infectious organisms (viruses, bacteria, intracellular parasites, fungi), whereas TH2 responses play a signicant role in mediating the response to multicellular and extracellular parasites. Precisely how TH1 versus TH2 dierentiation occurs is incompletely understood. A number of transcription factors such as GATA-3, nuclear factor of activated T cells and cMaf are evidently involved. It is also clear that cytokines themselves are important in this process, the most important being IL-12 and IL-4; IL-12 is a major factor that stimulates the dierentiation of precursor CD4 1 cells toward a TH1 phenotype, whereas IL-4 appears to play the key role in TH2 subset dierentiation. IL-2 is an autocrine T-cell growth factor required for progression of T cells through the cell cycle. It also augments the cytolytic activity of T and NK cells and induces IFNg secretion in NK cells. It is a growth factor for B cells, induces immunoglobulin class switching, and also activates macrophages. Thus IL-2 is an important factor which enhances the magnitude of the immune response. Interestingly, though, IL-2 and IL-2 receptor knockout mice manifest unrestricted lymphoproliferation and autoimmune phenomena, probably reecting the fact that IL-2 also serves to constrain lymphocyte growth by enhancing lymphocyte activation-induced cell death (AICD; see below). IL-15 has a number of eects similar to those of IL-2, primarily because it also binds to the IL-2 receptor; it is made by nonlymphoid cells, however IL-15 is essential for NK-cell development and memory T cells. IFNg is a major activator of macrophages; it enhances their ability to kill microorganisms, upregulates class II expression, and promotes TH1 dierentiation. Notably, IFNg also suppresses TH2 responses. It also acts on murine B cells to promote switching to immunoglobulin (Ig)G2a and IgG3, and inhibits switching to IgG1 and IgE. IFNg knockout mice have diminished macrophage MHC class II expression, decreased NK function, and increased susceptibility to pathogens, especially intracellular microbes; this is also true of humans with mutations of IFNg receptor subunits. IL-12, as mentioned above, is a major eector molecule in TH1 subset dierentiation. It also induces proliferation, augmentation of cytolytic activity and IFNg secretion in NK cells. IL-12 is produced by monocytes in response to pathogenic organisms; it is also produced by other cells such as B cells and dendritic cells. IL-18 is produced by activated macrophages and is an important inducer of IFNg. IL-18 knockout mice have impaired IFNg production, TH1 responses and NK cell activity.

ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / [Link]

Immunoregulation

Cytokine

Cytokine receptor

STAT

JAK

JAK

and bronectin by broblasts, and are thought to be responsible, in part, for diseases characterized by brosis such as systemic sclerosis and pulmonary brosis. Cells that predominantly produce IL-10 and TGFb have been termed TH3 (or T regulatory 1) cells. In summary, numerous cytokines are produced in an immune response and they have important eects on the behaviour of immune cells. Some facilitate the activation of lymphocytes through eects on APCs. Other cytokines act on lymphocytes and direct them to drive cell-mediated responses, and others promote allergic responses. Still others inhibit immune responses. Cytokine signal transduction

STAT P P STAT

Gene transcription

DNA

Figure 3 Signal transduction by type I and type II cytokines. Cytokines bind to the extracellular domain of transmembrane cytokine receptors, causing them to cluster. Janus kinases (JAKs) are protein tyrosine kinases that bind to the intracellular domain of cytokine receptors; the aggregation of receptors causes the JAKs to become activated. The activated JAKs phosphorylate substrates including the cytokine receptor. The phosphorylated receptor then is recognized by proteins that have specialized SH2 domains, which recognize phosphotyrosine. The signal transducer and activator of transcription (STAT) family of transcription factors have SH2 domains; they bind cytokine receptors and are themselves phosphorylated. The SH2 domains of the STATs allow them to dimerize, translocate to the nucleus, bind deoxyribonucleic acid (DNA) and regulate gene transcription.

In contrast to TH1 cells, TH2 cells promote responses associated with immediate hypersensitivity responses. IL-4 is made by CD4 1 TH2 cells and promotes dierentiation of naive CD4 1 cells to a TH2 phenotype. It is also a growth factor for mast cells and is required for class switching of B cells to produce IgE. Importantly, IL-4 inhibits macrophage activation and blocks the eects of IFNg. Regulation of the IL-4 gene is of great importance in dictating what kind of immune response will ensue. Consequently, a number of transcription factors contribute to its regulation. IL-13 has many of the same eects as IL-4 and even shares a receptor subunit(s) with IL-4, thus it too contributes to TH2 responses. TH2 cells also produce IL-5, which promotes the growth, dierentiation and activation of eosinophils. IL-10 and the TGFb family are cytokines that antagonize lymphocyte responses. TGFbs also induce collagen

Cytokines that bind receptors belonging to the type I and type II cytokine receptors superfamily have several common features in their mechanisms of signal transduction. One common feature is that they activate members of a family of cytoplasmic protein tyrosine kinases known as Janus kinases (JAKs; Figure 3 and Table 2), which bind cytokine receptors, become activated following cytokine binding to the receptor, and phosphorylate cytokine receptor subunits. These phosphorylated tyrosine residues recruit proteins with modules that bind phosphotyrosine (for instance, SH2 domains), one critical family of which is the signal transducers and activators of transcription (STATs) family of transcription factors. These proteins bind the phosphorylated receptor subunits, become phosphorylated themselves, dimerize and translocate to the nucleus where they regulate gene expression. Dierent cytokines activate dierent STAT proteins (Table 2). The specic and nonredundant functions of the dierent STATs are exemplied by the dierent STAT knockout mice (Table 3). STAT1-decient mice are highly susceptible to viral infection because they lack responsiveness in interferons. In contrast, STAT4-decient knockout mice have defective TH1 dierentiation due to abrogation of IL12 responses, whereas STAT6-decient mice have marked impairment in TH2 development due to disruption of IL-4 and IL-13 signalling. These mice convincingly demonstrate the essential role of STATs in immunoregulation.

Programmed cell death or apoptosis

Upon recognition of a pathogen, immune cells are activated and produce cytokines. Typically, this response leads to the destruction and removal of the oending organism. Subsequently the immune response is turned o; indeed, a fundamental characteristic of immune responses is that they are self-limiting. A major mechanism by which this occurs is through a process termed programmed cell death, cell suicide or apoptosis. The importance of apoptosis in the developmental programmes of many species, from worms to human, is now well documented. Immune cells, though, rely heavily on these process.
5

ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / [Link]

Immunoregulation

Table 2 Activation of Janus kinases and signal transducers and activators of transcription by cytokines Cytokine Type I cytokines gp130-using cytokines IL-6, IL-11, oncostatin M, leukaemia inhibitory factor, ciliary neurotrophic factor, cardiotropin-1 IL-12a c-using cytokines IL-3, IL-5, GM-CSF c-using cytokines IL-2, IL-7, IL-9, IL-15 IL-4b IL-13b Hormones Growth hormone Prolactin Erythropoietin, thrombopoietin Leptin Type II cytokines IFN/ (type I IFNs) IFN (type II IFN) IL-10c
a b

JAK

STAT

JAK1, JAK2, TYK2 JAK2, TYK2 JAK2 JAK1, JAK3 JAK1, JAK3 JAK1, JAK2, TYK2 JAK2 JAK2 JAK2

STAT3 STAT4 STAT5a, STAT5b STAT5a, STAT5b, STAT3 STAT6 STAT6 STAT5a STAT5b STAT5a, STAT5b STAT3

JAK1, TYK2 JAK1, JAK2 JAK1, TYK2

STAT1, STAT2, STAT4 STAT1 STAT3

Interleukin (IL) 12 does not use glycoprotein 130, but its receptor subunits are homologous to it. IL-4 can form two types of receptor, one with the common g subunit (gc) and one with the IL-13 receptor. c IL-10 is not an interferon (IFN), but its receptor is most similar to IFN receptor subunits. GM-CSF, granulocytemacrophage colony-stimulating factor; gp130, glycoprotein 130; JAK, Janus kinase; STAT, signal transducer and activator of transcription; TYK2, tyrosine kinase 2.

Table 3 Characteristics of JAK and STAT knockout mice Knockout JAKs JAK1 JAK2 JAK3 STATs STAT1 STAT2 STAT3 STAT4 STAT5a STAT5b STAT6 Pathology Perinatal lethal, SCID Embryonic lethal, defective haematopoiesis SCID Impaired signalling by gc and gp130 cytokines, IFNs bc cytokines, erythropoietin, thrombopoietin, IFNg gc cytokines

Viral susceptibility Not reported Embryonic lethal Defective TH1 response Impaired mammary gland development Defective sexually dimorphic growth responses Defective TH2 responses

IFNa/b, IFNg

IL-12 Prolactin Growth hormone IL-4, IL-13

bc, common b subunit; gc, common g subunit; gp130, glycoprotein 130; IFN, interferon; IL, interleukin; JAK, Janus kinase; SCID, severe combined immune deciency; STAT, signal transducer and activator of transcription; TH, T helper cell.

ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / [Link]

Immunoregulation

There are probably a number of ways in which apoptosis is regulated by lymphocytes, but two important means are cytokine withdrawal apoptosis and AICD. That is, if the oending antigen is removed, TCR-dependent activation subsides and cytokine production falls. The needs of the expanded lymphocyte population then begin to outstrip cytokine production. Lymphocytes begin to starve, and this can initiate programmed cell death. Cytokine withdrawal apoptosis is also called death by neglect or passive cell death to contrast it with AICD. AICD is another important mechanism for dampening the immune response and is mediated by the interactions of the membrane molecules Fas (CD95) and Fas ligand (FasL). Fas membrane protein is expressed on lymphoid and other cells but is increased in expression with cellular activation. Its ligand, FasL, another membrane protein, is expressed on activated T cells; thus, activation of T cells results in the expression of both Fas and FasL. The intracellular portion of the Fas receptor molecule contains death domains, which recruit proteins that lead to the activation of a cascade of proteases (termed caspases) which induce apoptosis. FasFasL interaction is a major means of mediating AICD in CD4 1 cells. Thus, it is now clear that accompanying lymphocyte activation and proliferation is substantial lymphocyte apoptosis due to either cytokine starvation or FasFasLmediated caspase activation; indeed, it is quite apparent that this is a major aspect of immunoregulation. The selflimiting nature of immune responses is an essential part of immune homeostasis; programmed cell death provides an excellent mechanism for elimination of lymphocytes after the oending antigen has been cleared. The critical function of this mechanism is exemplied in two types of knockout mice. In mice lacking the IL-2Ra chain (or IL-2), there is impressive lymphoproliferation and concomitant autoimmunity, illustrating the essential role of IL-2 in constraining lymphocyte proliferation. In addition, mice with mutations of Fas or FasL also have extensive lymphoproliferative disease, as do humans with mutations of Fas (see below).

Thus, despite this large body of experimental data, it is tempting to conclude at this point that a unique population of suppressor cells does not exist and that most of the previously measured suppressor activity can be explained by cytokine production. Antiidiotypic regulation Another theory of immunoregulation was the network hypothesis of regulation. In an immune response a clone (or clones) of lymphocytes is expanded in response to a specic antigen. It was theorized that lymphocytes exist with receptors that recognize the antigen receptors on the rst clonally expanded population of lymphocytes. This second population of lymphocytes was proposed to expand and control the response of the rst population. This was called the antiidiotypic response. Although antiidiotypic responses can be detected experimentally, there are few data to support this mechanism as an important aspect of immunoregulation, especially for T cells.

Immunoregulation in Infectious, Allergic Autoimmune Disease and Immunodeficiency

Immune response to pathogenic organisms: protection and damage
The cellular immune response (also termed delayed-type hypersensitivity or cell-mediated immunity) is the primary defence against intracellular pathogens and can be summarized as follows. Sentinel cells, such as tissue-based macrophages and dendritic cells, engulf these pathogens and presumably migrate to the regional lymph node where they present the antigen to naive T cells. In so doing, they also produce IL-12, which aids in the development of a TH1 response. Activated T cells produce IL-2, IFNg, LT and chemokines. IFNg in turn activates macrophages, enhancing their ability to kill the intracellular pathogens. TH1 cytokines also cause the recruitment and activation of other leucocytes from the circulation. The cellular immune response to viral infections can be summarized as follows: viral infection induces type I IFN production, which in turn inhibits viral replication and cell proliferation. It also upregulates MHC class I expression, facilitating presentation of viral peptide antigens CD8 1 T cells, which become activated and lyse the cells. In addition, type I IFN activates NK cells, which also kill virally infected cells. Interestingly, viruses have evolved a number of strategies for evading the immune response including interfering with presentation of viral antigens. Fortunately, NK cells also recognize cells that lose MHC class I and kill them.
7

Older proposed mechanisms of immunoregulation

Suppressor cells Lymphocytes capable of suppressing immune responses were described in the 1970s. It was initially thought that, whereas CD4 1 cells were the helper subset, CD8 1 cells represented the suppressor and cytotoxic subsets. However, despite numerous attempts to isolate suppressor cells, no population with exclusive suppressor activity has been found. Now we know that many cytokines are produced, some of which amplify (IL-12) and some of which suppress (TGFb and IL-10) immune responses. Still others, like IL4, amplify some (TH2) and inhibit other (TH1) responses.

ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / [Link]

Immunoregulation

After eradication of the pathogen, the immune response generally subsides without damage to the host tissue because of the production of cytokines like TGFb and IL10, and because of apoptosis of lymphocytes. However, this is not necessarily the case; a normal immune response itself may cause considerable damage to the host simply because of its attempt to contain a microorganism. Cellmediated immunity contributes to disease pathogenesis in a variety of ways. Vigorous production of TNFa can cause septic shock or lung disease, termed adult respiratory distress syndrome. Thus, sometimes patients die not from the infection but from the immune response to the infection. In addition, the cell-mediated responses to Mycobacterium tuberculosis infection or parasitic infestations can also extensive tissue destruction. Role of T-cell subsets in the response to parasites As the relationship between parasites and the hosts immune system becomes elucidated better, it is becoming clear that there is a ne balance between mounting a protective immune response and one that induces pathology. In some parasitic infections, in fact, morbidity may be due to the immune or inammatory response induced. It is apparent that both type 1 (TH1) and type 2 (TH2) responses can, depending on the conditions, incite tissue damage during parasitic infection. Parasitic infections can be broadly classied into those caused by protozoa (unicellular organisms) and those by helminths (multicellular organisms). Both types of parasites have adopted numerous strategies for evading or modulating the host immune response so that chronic infections can be established. Cellular immune responses to protozoa, at least, induce a broad range of cytokines from host cells that are instrumental in controlling growth of the parasite and in restricting acute disease, although excess production can contribute quite substantially to the pathology caused by infection with these parasites. In general, however, it can be assumed that the protozoan parasites typically induce a TH1 (or type 1 response) which, for the most part, is protective. This is certainly true for Toxoplasma gondii infection, the cutaneous forms of leishmanial infections, cryptosporidial infections, and probably for malaria once protection is established. Interestingly, when there is a failure of TH1 responses to be induced by these parasites (or when there is a loss of TH1 cells, as occurs in the late stages of human immunodeciency virus infection) the immunological resistance against these parasites is abrogated and growth of the parasitic protozoa goes unchecked (e.g. visceral leishmaniasis or disseminated cutaneous leishmaniasis). This has parallels in the Mycobacterium leprae infections in which the lepromatous form of leprosy is associated with unrestricted growth of the organism and with an inability to mount a TH1-type response, which contrasts markedly with the less progressive forms of the infections (tubercu8

lous leprosy) in which not only is there characteristically a TH1-type response to the organism, but also there is a control of organism growth. Nevertheless, for some protozoal infections cytokine responses have been associated with severe morbidity, the most notable being the direct relationship between TNFa levels and the most severe form of malaria (cerebral malaria). For the helminth infections it is less well established how cellular immune responses mediate immunity to infection or reinfection. While various immune eector mechanisms (IgE, eosinophils, mast cells) are invoked by infection with helminth, mainly mediated by the TH2 type of cytokines, because these infections remain established within the host, often for decades, the concept of true sterile immunity to these multicellular worms remains in question. With chronic helminth infections, such as schistosomiasis, onchocerciasis and lymphatic lariasis, antigen-specic T-cell proliferation and IL-2 and IFNg (TH1 cytokines) are also depressed, whereas the production of IL-4 and IL-5 is consistently raised. Regulation of this TH1 response occurs primarily through the production of counterregulatory cytokines such as IL-10 and transforming growth factor b. This lack of TH1 responsiveness appears to prevent parasite clearance, although murine models of human intestinal helminth infection suggest that TH2 responses may be crucial for resistance to occur. In addition to playing a role in immunity to gastrointestinal helminths, there is strong epidemiological evidence that type 2 responses (or at least IgE) may mediate the resistance to schistosomiasis. Consistent with this general hypothesis, data from eld studies in Brazil indicate that the ability to resist infection is inuenced by a major gene that localizes to a region of chromosome 5 which encodes type 2 cytokines. While mediating this resistance phenomenon, it is also likely that these type 2 responses also mediate the granulomatous reactions around the schistosome eggs, responses that cause the pathological ndings seen in schistosomiasis. Thus, it appears that, for all parasitic infections, the balance between proinammatory cytokine responses and those that mediate protection is the major determinant of outcome. Regulation of the immune response in allergic diseases and asthma Allergic diseases are characterized by localized and/or systemic immune responses associated with immediate hypersensitivity, including IgE production, peripheral or tissue eosinophilia, and the presence of inammatory mediator-rich mast cells and basophils. Using approaches that examine expression of either cytokines or messenger ribonucleic acid for cytokines, it has become increasingly clear that allergen-specic T cells that express IL-4, IL-5, IL-13 and IL-10 play a signicant role in the pathogenesis of allergic diseases and asthma. Indeed, overproduction of the TH2-type cytokines represents an inappropriate

ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / [Link]

Immunoregulation

response to environmental antigens, and mediates or at least prolongs allergic responses and late-phase reactions associated with airway hyperreactivity, allergic rhinitis and atopic skin disease. However, it must be mentioned that these cytokines do not always derive from T-cell sources and it may be the aggregate expression of the various cytokines in situ that determines the nature of the response at site of allergic inammation. Nevertheless, regulating the overproduction of IL-4, IL-5 and IL-13 by other cytokines (IL-12, IL-18, IFNg) or by inducing tolerance or apoptosis to the oending allergen is now undergoing evaluation. There also appears to be a genetic predisposition to the development of allergic diatheses. Although this is likely to involve more than one gene (complex genetic trait), there is likely to be a genetic susceptibility to the production of a predominant TH2-type cytokine response to particular allergens. Linkage to a region of chromosome 5q31.1, a region that includes genes for IL-4, IL-5 and IL-13, has been found in patients with high levels of IgE and bronchial hyperreactivity. More recently a mutation in the IL-4 receptor has been found in some patients with allergies; precisely how this contributes to disease needs to be unravelled.

Immunodeficiency and immunoregulation

Immunodeciency occurs when the key elements of the cell-mediated immune response do not function appropriately. For instance, TCR signalling is a key step in lymphocyte activation, and severe combined immune deciency (SCID) can occur because of the absence of the TCR-associated kinase, zeta-associated protein of 70 kDa (ZAP-70). The importance of the receptors and kinases responsible for transmitting signals from cytokine binding is underscored by two other forms of SCID. One form is due to mutation of the common g subunit (gc), a constituent of the receptors for IL-2, IL-4, IL-7, IL-9 and IL-15. In gc deciency, signalling via all these cytokines is disrupted, resulting in failure of the immune system to develop and function properly. The gc subunit is found on the Xchromosome and the immunodeciency is termed XSCID. It accounts for about half of the cases of SCID. The gc subunit binds JAK3 and the gc cytokines (IL-2, IL-4, IL-7, IL-9 and IL-15) all activate this JAK. Deciency of JAK3 also leads to a form of SCID that is identical to XSCID, except that girls and boys are both aected since the JAK3 gene resides on chromosome 19. Recently patients have been identied with mutations of IFNgR subunits and the IL-12Rb1 subunit. These patients become infected with pathogens that usually do not harm individuals with normally functioning immune systems, illustrating the importance of IFNg and IL-12 in cellmediated responses. Most recently, patients with mutations of the TNF receptor (TNFR) have been identied and they suer from recurrent fevers; this is apparently due to the inability to produce soluble TNFR which inhibits the inammatory response.

Immunoregulation and the pathogenesis of autoimmune diseases

For the most part, we are rather ignorant of the pathogenesis of most autoimmune diseases. None the less, our understanding of these disease is steadily improving. It is well recognized that the development of autoimmune disease is heavily inuenced by molecules such as the MHC and TCR, which are involved in antigen recognition. We also know from animal models that deciencies of a variety of antiinammatory cytokines like TGFb and IL-10, or even IL-2, can lead to autoimmune disease. In addition, the overproduction of cytokines has been documented in many human autoimmune diseases as well as in animal models. For instance, patients with rheumatoid arthritis have high levels of TNFa and IL-6. Exactly why these cytokines are produced is not known. Some forms of arthritis are associated with infections, but how and why joints become damaged is still poorly understood; animal models will be key to dissecting the mechanisms involved in these diseases. The importance of apoptosis in controlling immune responses is well supported by the discovery of humans with Fas mutations; the disease is termed autoimmune lymphoproliferative syndrome. Thus, although we do not understand autoimmune and allergic diseases well, there are many clues that point to dysregulation of immune responses as a major contributor to the pathogenesis of autoimmune disease.

Exploiting our understanding of immunoregulation to treat disease

An understanding of how the immune response is regulated allows strategies to be devised which either enhance cellular immune responses (e.g. production of better vaccines) or inhibit immune responses (e.g. prevention of transplant rejection). Some of these strategies will be discussed briey. Cytokines, in particular, are widely used at present. Some colony-stimulating factors (CSFs) are presently used clinically for their prohaematopoietic properties, including erythropoietin, granulocyte (G) CSF and granulocyte macrophage (GM) CSF; it is anticipated that in the near future others will also be used. IFNa/b is used clinically in the treatment of certain infections such as chronic hepatitis B. In addition, it is used in the treatment of certain malignancies (e.g. hairy cell leukaemia) because of its antiproliferative eects. IL-2 is used in certain cancers to increase antitumour responses and is also used in patients
9

ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / [Link]

Immunoregulation

with acquired immune deciency syndrome to enhance immune responses. In contrast, anti-IL-2R antibody is used to treat transplant rejection. Similarly, interfering with TNFa action has been used therapeutically; in particular, recent studies have demonstrated the ecacy of TNF antagonists in treating rheumatoid arthritis. TNF antagonists have also been used in the treatment of septic shock. Conversely, the immunosuppressive cytokine IL-10 is now also being used experimentally in the treatment of autoimmune disease. In addition, blocking costimulatory molecules has also been used experimentally in models of autoimmune disease and transplant rejection.

basic science give us better opportunities to manipulate the immune system in a therapeutically desirable manner.

Further Reading
Abbas AK, Lichtman AH and Pober JS (1997) Cellular and Molecular Immunology, 3rd edn. Philadelphia: W.B. Saunders. Kuo CT and Leiden JM (1999) Transcriptional regulation of T lymphocyte development and function. Annual Review of Immunology 17: 149188. Leonard WJ and OShea JJ (1998) Jaks and STATs: biological implications. Annual Review of Immunology 16: 293322 Matzinger P (1994) Tolerance, danger and the extended family. Annual Review of Immunology 12: 9911045. McDermott MF, Aksentijevich I, Galon J et al. (1999) Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, dene a family of dominantly inherited autoinammatory syndromes. Cell 97: 120. OGarra A (1998) Cytokines induce the development of functionally heterogeneous T helper cell subsets. Immunity 8: 275283. OShea JJ (1997) Jaks, STATs, cytokine signal transduction, and immunoregulation: are we there yet? Immunity 7: 111. Parijs LV and Abbas A (1998) Homeostasis and self-tolerance in the immune system: turning lymphocytes o. Science 280: 243248. Paul WE (1999) Fundamental Immunology. New York: Raven Press. Rosen FS, Cooper MD and Wedgwood RJ (1995) The primary immunodeciencies. New England Journal of Medicine 333: 431440. Schwartz RH (1996) Models of T cell anergy: is there a common molecular mechanism? Journal of Experimental Medicine 184: 18. Szabo SJ, Glimcher LH and Hoi IC (1997) Genes that regulate interleukin-4 expression in T cells. Current Opinion in Immunology 9: 776781. Wang J and Lenardo MJ (1997) Molecules involved in cell death and peripheral tolerance. Current Opinion in Immunology 9: 818825.

Summary
In conclusion, the vertebrate immune response is the ultimate smart bomb. Its ability to respond to antigen is nely tuned genetically and is modied by signals from receptors that transmit both activating and inhibitory signals. The functions of immune cells are closely controlled by secreted factors termed cytokines which can amplify, inhibit or shape the response. Finally, programmed cell death or apoptosis carefully regulates the number of circulating lymphocytes. Clearly, advances in our understanding of the molecular basis of immunoregulation have provided and will continue to provide important insights into the pathogenesis of immunologically mediated disease, whether they be immunodeciencies or autoimmune diseases. Finally, these advances in

10

ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / [Link]